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Human aromatase (CYP19) pharmacogenomics: Gene resequencing and functional genomics
Abstract
Background/AimsCYP19 is a key enzyme in estrogen biosynthesis. CYP19 inhibitors are used to treat breast cancer. We set out to identify and characterize genetic polymorphisms in CYP19 as a step toward pharmacogenomic studies of aromatase inhibitors.Methods
We resequenced the CYP19 5′-untranslated exons PII and 1.3, as well as the 9 coding exons (exons 2 to 10), intron-exon splice junctions and portions of the 3'-untranslated region in 240 DNA samples from 4 ethnic groups.Results28 polymorphisms were identified. Functional genomic studies were performed with the 4 nonsynonymous coding SNPs which altered the following amino acids: Trp39Arg, Thr201Met, Arg264Cys, and Met364Thr. The Cys264, Thr364 and the double variant Arg39,Cys264 allozymes showed significant decreases in levels of activity and enzyme protein after transient expression in COS-1 cells. A 4-fold increase in apparent Km was observed for Thr364 with androstenedione as substrate. None of the recombinant allozymes had significant changes in Ki values for the aromatase inhibitors exemestane and letrozole.Conclusions
Genetic variation in CYP19 might contribute to variation in the occurrence of estrogen-dependent disease and/or response to aromatase inhibitors.Clinical Pharmacology & Therapeutics (2005) 77, P22-P22; doi: 10.1016/j.clpt.2004.11.085
... Aromatase is encoded by the CYP19A gene. Its transcription is tightly regulated through: tissue-specific promoter sequences [23]; the presence or absence of one or more single nucleotide polymorphisms (SNPs) [25,26]; and through hypoxia [27]. Since it has been suggested that impaired placental perfusion is responsible for the molecular events leading to the clinical manifestations of PE8910, we propose to investigate the expression and function of aromatase in normal and PE pregnancies in an in vitro model of hypoxia and in an in vivo model of placental ischemia. ...
... They maintain that PE is rather the result of a failure of villous trophoblast differentiation that leads to an abnormal release of trophoblast material (microparticles and other toxins) into the maternal circulation [16]. Another mechanism by which aromatase expression and activity may be altered is through the presence of SNPs within its promoter region [25,26]. Of particular interest are the SNPs in exon 1 of CYP19A (known as the placenta-specific aromatase regulator) that have been associated with specific changes in aromatase activity within the placenta as well as alterations in circulating concentrations of 17-β-estradiol [25]. ...
... Another mechanism by which aromatase expression and activity may be altered is through the presence of SNPs within its promoter region [25,26]. Of particular interest are the SNPs in exon 1 of CYP19A (known as the placenta-specific aromatase regulator) that have been associated with specific changes in aromatase activity within the placenta as well as alterations in circulating concentrations of 17-β-estradiol [25]. We have measured three placental aromatase SNPs (rs4646, rs10046 and rs6493497)434445 , each of which regulates the activity of the aromatase enzyme. ...
Introduction:
Preeclampsia is a maternal hypertensive disorder with uncertain etiology and a leading cause of maternal and fetal mortality worldwide, causing nearly 40% of premature births delivered before 35 weeks of gestation. The first stage of preeclampsia is characterized by reduction of utero-placental blood flow which is reflected in high blood pressure and proteinuria during the second half of pregnancy. In human placenta androgens derived from the maternal and fetal adrenal glands are converted into estrogens by the enzymatic action of placental aromatase. This implies that alterations in placental steroidogenesis and, subsequently, in the functionality or bioavailability of placental aromatase may be mechanistically involved in the pathophysiology of PE.
Methods:
Serum samples were collected at 32-36 weeks of gestation and placenta biopsies were collected at time of delivery from PE patients (n = 16) and pregnant controls (n = 32). The effect of oxygen tension on placental cells was assessed by incubation JEG-3 cells under 1% and 8% O2 for different time periods, Timed-mated, pregnant New Zealand white rabbits (n = 6) were used to establish an in vivo model of placental ischemia (achieved by ligature of uteroplacental vessels). Aromatase content and estrogens and androgens concentrations were measured.
Results:
The protein and mRNA content of placental aromatase significantly diminished in placentae obtained from preeclamptic patients compared to controls. Similarly, the circulating concentrations of 17-β-estradiol/testosterone and estrone/androstenedione were reduced in preeclamptic patients vs. controls. These data are consistent with a concomitant decrease in aromatase activity. Aromatase content was reduced in response to low oxygen tension in the choriocarcinoma JEG-3 cell line and in rabbit placentae in response to partial ligation of uterine spiral arteries, suggesting that reduced placental aromatase activity in preeclamptic patients may be associated with chronic placental ischemia and hypoxia later in gestation.
Conclusions:
Placental aromatase expression and functionality are diminished in pregnancies complicated by preeclampsia in comparison with healthy pregnant controls.
... The key enzymes of ovarian steroidogenesis are hydroxylases and oxidases, which belong to a large family of cytochrome P450 [1][2][3][4] that consists of 480 enzymes, including i) P450scc, which is responsible for cleaving the side chain of cholesterol, ii) P450c11, which mediates the conversion of 11-deoxycorticosterone to corticosterone and possesses 11-hydroxylase, 18-hydroxylase, and 19-methylooxydase activities, iii) P450c17, which mediates 17-hydroxylation of pregnenolone and progesterone, iv) P450c21, which has 21-hydroxylase activity, and v) aromatase cytochrome P450, whose activity directs aromatisation of androgens to estrogens [4][5][6][7][8]. Steroidogenesis includes a few characteristic reactions such as i) side-chain cleavage as a result of desmolase activity, ii) conversion of hydroxyl groups to ketone groups mediated by dehydrogenase, and iii) addition of hydroxyl groups (hydroxylation) by a reaction involving the formation of double bonds (removing hydrogen atoms) and saturation (adding hydrogen atoms) [3,4]. ...
... The most important step in women's steroidogenesis is aromatisation of androgens, which leads to the generation of estrogens. This process is mediated by aromatase cytochrome P450 and is observed in the endoplasmic reticulum of granulosa cells in many steroidogenic and non-steroidogenic tissues and glands, including the ovaries, placenta, adipose tissue, hair, vascular smooth muscle, skin, liver, bones (osteoblasts), and blood vessels [4][5][6]8,9]. ...
... This name reflects enzymatic oxidation of the methyl group at C-19 [3,4,10]. In the ovary, aromatase cytochrome P450 catalyzes conversion of testosterone (T) to estradiol (E 2 ), androstendione (A) to estrone (E 1 ), and 16α-hydroxylated dehydroepiandrosterone (DHEA) to estriol (E 3 ) [5,6,11]. In women of reproductive age, 70% of the E 1 and over 95% of the E 2 circulating in serum are ovary-derived [4,8]. ...
Background
Menopause results in a lack of regular menstrual cycles, leading to the reduction of estrogen production. On the other hand, ovarian androgen synthesis is still present at reduced levels and requires expression of several steroidogenic enzymes.
Methods
This study was performed on 104 postmenopausal women hospitalized due to uterine leiomyomas, endometriosis, and/or a prolapsed uterus. Patients were divided into three groups depending on the time from menopause. Group A patients experienced menopause 1–5 years before enrollment in the study (42 women). Group B included women who had their last menstruation 5–10 years before the study (40 women). Group C consisted of 22 women who were more than 10 years past menopause. Hysterectomy or removal of the uterine corpus with adnexa was performed during laparotomy. We evaluated the expression of aromatase cytochrome P450 (CYP 19) and 17β-hydroxysteroid dehydrogenase (17β HSD) by employing immunohistochemistry.
Results
Activity of 17β-HSD and CYP19 was demonstrated in the cytoplasm of stromal cells of postmenopausal ovaries, epithelium cells coating the ovaries, vascular endothelial cells, and epithelial inclusion cysts. However, overall expression of both 17β-HSD and CYP 19 decreased with time after menopause.
Conclusion
Demonstration of the activity of the key enzymes of ovarian steroidogenesis, CYP 19 and 17β-HSD, confirms steroidogenic activity in the ovaries of postmenopausal women. Nevertheless, ovarian steroidogenic activity decreases with time, and its significant decrease occurs 10 years after menopause.
... The C/C, C/T and T/T genotypes of Arg264Cys variant were observed in 59%, 33%, and 9% of control patients and in 45% 42% and 14% of cases respectively. Thus the high prevalence of T allele of Arg264Cys polymorphism seems to be a characteristic in Asian populations (Suzuki et al. 2003a, Ma et al. 2005. According to Suzuki et al. (2003a), the presence of at least one T allele was associated with prostate cancer risk (OR=1.77; ...
... The combined frequencies of C/T and T/T genotypes were 9%, 12% and 8% among unselected prostate cancer cases, familial prostate cancer cases and population controls respectively. Two studies report that the Cys246 variant was similar to the wild type enzyme with regard to substrate and inhibitor kinetics (Watanabe et al. 1997, Ma et al. 2005. Watanabe et al. (1997) claimed that aromatase activity was not affected by Cys264, whereas Ma et al. (2005) observed a slight decrease in the enzyme activity of this variant. ...
... Two studies report that the Cys246 variant was similar to the wild type enzyme with regard to substrate and inhibitor kinetics (Watanabe et al. 1997, Ma et al. 2005. Watanabe et al. (1997) claimed that aromatase activity was not affected by Cys264, whereas Ma et al. (2005) observed a slight decrease in the enzyme activity of this variant. The studies were otherwise identical, but Watanabe et al. (1997) used cytosolic marker enzyme to correct for transfection efficiency, whereas in the study by Ma et al. (2005), a fusion protein targeted at the endoplasmic reticulum was used. ...
... More than 80 CYP19 polymorphisms have been described (10). Of these, the most extensively studied are the intron 4 short tandem repeat tetranucleotide (TTTA)n and TCT insertion/deletion (TCT I/D) polymorphisms located 50 bp upstream of the (TTTA)n repeat. ...
... Genotyping CYP19 polymorphism data from controls (Table 2) revealed that genotype frequencies were in Hardy-Weinberg equilibrium (PO0.05). The observed CYP19 alleles distribution is similar to those reported in other Caucasian male populations (10,12,14,16,19). ...
Aromatase cytochrome P45019 (CYP19) is a key enzyme in estrogen biosynthesis, and polymorphisms within its gene are associated with an increased risk of estrogen-dependent diseases. Enhanced estrogen stimulation of breast tissue in men may lead to gynecomastia. We assessed whether intron 4 (TTTA)n repeat and TCT deletion/insertion polymorphisms and an exon 10 (3'-UTR) C/T single nucleotide polymorphism of CYP19 are associated with gynecomastia.
We performed a genetic association study of 100 patients referred to the endocrinological outpatient clinic with breast glandular tissue enlargement confirmed by clinical and ultrasound examinations and 99 healthy volunteers without gynecomastia. Microsatellite (TTTA)n and insertion/deletion polymorphisms were studied using capillary electrophoresis, and the C/T polymorphism in the 3'-UTR was analyzed using the TaqMan assay.
Significantly increased risk of gynecomastia was found in subjects carrying a CYP19 exon 10 T allele that was previously related to the high aromatase activity. Frequency of the TT genotype was significantly higher in patients when compared with controls (40.6 vs 26.3%; TT versus CT and CC genotypes; P(c)<0.05). We found strong linkage disequilibrium between the alleles of studied polymorphic loci. T allele in the 3'-UTR was in linkage disequilibrium with the long alleles of the intron 4 polymorphism, mainly (TTTA)11. However, our findings did not show significant correlation of alleles having more than nine TTTA repeats with gynecomastia.
The CYP19 polymorphisms might contribute to the incidence of gynecomastia, but further studies in larger groups are needed to confirm these results.
... Previous population-based studies of common CYP19 polymorphisms have generated inconsistent results with regard to their possible association with either sex hormone levels or risk for estrogendependent diseases. Selected CYP19 polymorphisms have also been investigated for their possible association with the therapeutic efficacy of aromatase inhibitors (Ma et al., 2005). Maia et al. found that aromatase expression in the endometrium was associated with the presence of dysmenorrheal and endometriosis and there was a tendency for aromatase expression to be positively correlated with dysmenorrheal severity (Maia Jr et al., 2012). ...
This study is designed to investigate the relationship between oxidative stress and single nucleotide polymorphism G/T rs4646 of CYP19 and determine the main effects of SNP on the gene expression in Iraqi women with endometriosis disease. Data were collected from sixty women, mean age (31.16 ± 5.61) years as referred by a Gynecologist for endometriosis investigation. A total of thirty healthy female volunteers served as control, mean age (31.96 ± 5.42) years. The results revealed a highly significant increased (P < 0.01) in the malondialdehyde (MDA). The results of the Coenzyme Q10 vitamin A, β-carotene and vitamin E showed a highly significant decreased (P < 0.01) in the sera levels of women with endometriosis as compared to control. The results showed a significant (P ≤ 0.01) association between oxidative stress and selected SNP of CYP19 gene. No significant differences (P > 0.05) were observed in the level of LH, FSH, and Testosterone among different genotypes, while a significant increase (P < 0.05) in the level of E2 in women have TT genotype. A highly significant difference (P ≤ 0.01) in CYP19 gene expression from women with versus without endometriosis and increased by 3.82-fold in women with endometriosis. In this regard, we suggest that decreased of antioxidant vitamins and increased of MDA have an effect on the production of ovarian steroid hormones, in particular CYP19 gene, which encodes aromatase that is the key enzyme for estrogen biosynthesis. We deduce that CYP19 gene polymorphism is associated with the presence of endometriosis and can be considered a potential biomarker of the disease. Our findings may lead to new insights into the manner of development of endometriosis disease. The association between SNP G/T rs4646 of CYP19 and MDA suggest that SNP may play important role in the ovarian antioxidant-oxidant balance.
... To the extent that protection against masculinization for female callitrichines is mediated partly by modified SHBG, we would expect the NSs to increase either sex steroid affinity or production of the binding protein. SNPs that lead to reductions in efficacy or loss-of-function for enzymes involved in steroid biosynthesis have been documented for both CYP19A1 [44][45][46]and SRD5A2 [47][48][49], and these changes produce an undermasculinized phenotype in males. Our data revealed a callitrichine-specific NSs in SRD5A2 at protein position 49 (A49S), and polymorphisms at this position in human alter aromatase activity in bioassay and produce hypospadic phenotypes in males [50][51][52][53] . ...
Background:
Sexual differentiation in female mammals can be altered by the proximity of male littermates in utero, a phenomenon known as the intrauterine position effect (IUP). Among simian primates, callitrichines (marmosets and tamarins) are likely candidates for IUP, since they exhibit obligate dizygotic twinning and fetuses share extensive vascularization in utero. In this paper, we determined whether female reproductive parameters are altered by gestating with a male twin and evaluated changes in genes associated with anti-Müllerian and steroid hormones in twinning callitrichine primates.
Methods:
We assessed the impact of gestation with male cotwins on reproductive performance and survivorship in female marmosets (Callithrix) and lion tamarins (Leontopithecus), contrasting measures for females gestated with one or more littermates (M+) or no male littermates (0M). We compared targeted coding regions for genes involved in steroidal and anti-Müllerian hormone mediation of sexual differentiation for representatives of twinning callitrichines (Callithrix, Saguinus, and Leontopithecus) with closely related New World primates that produce single births (Saimiri and Callimico).
Results:
IUP effects in females were absent in female callitrichine primates: age at first ovulation, average litter size, and the proportion of stillborn infants, and lifetime survivorship did not differ between M+ and 0M females. We documented multiple nonsynonymous substitutions in genes associated with steroid synthesis, transport, and cellular action (SRD5A2, CYP19A1, SHBG, and AR) and with anti-Müllerian hormone (AMH and AMHR2) in callitrichines. In the only callitrichine to produce single infants (Callimico), two genes contained nonsynonymous substitutions relative to twinning callitrichines (CYP19A1 and AMRHR2); these substitutions were identical with nontwinning Saimiri and humans, suggesting a reversion to an ancestral sequence.
Conclusions:
In spite of a shared placental vasculature with opposite-sex twins throughout embryonic and fetal development, female callitrichine primates gestated with a male cotwin exhibit no decrement in reproductive performance relative to females gestated with female cotwins. Hence, IUP effects on female reproduction in callitrichines are modest. We have identified mutations in candidate genes relevant for steroid hormone signaling and metabolism, and especially in AMH-related genes, that are likely to alter protein structure and function in the callitrichines. These mutations may confer protection for females from the masculinizing and defeminizing influences of gestating with a male cotwin.
... RNA was reverse transcribed using oligodT and Moloney murine leukemia virus reverse transcriptase (Catalogue No. 210210; Qiagen). Amplification of ER-α and the housekeeping gene β-actin was then performed [12]. Polymerase chain reaction products were analyzed by agarose gel electrophoresis. ...
Cancer-Associated Fibroblasts (CAFs) are crucial in genesis and progression of tumors; however, cervical CAFs (C-CAFs) are not well characterized. Estradiol (E2) has been implicated as a cofactor in human papillomavirus (HPV)-mediated cervical cancer (CxCa), both in animal models and in women using oral contraceptives; however, the exact role of the hormone is unclear. Human C-CAFs have recently been shown to express estrogen receptor alpha (ER-α). We investigated gene expression patterns in ex vivo cultured early and late stage C-CAFs in the context of E2. CAFs were isolated from four patients with early and two patients with late stage CxCa. ER-α expression in CxCa tissues was localized to stromal fibroblast-like cells and confirmed in ex vivo cultured C-CAFs. Two ER antagonists (ICI 182,780 and Methyl Piperidino Pyrazole) were used to unravel ER signaling in CAFs. Microarray technology was used for expression profiling and validated by quantitative reverse transcription PCR. The transcriptomes of C-CAFs across stages indicated their activated state. C-CAFs had gene expression patterns associated with both pro-tumorigenic and pro-inflammatory signaling. Late-stage C-CAFs compared to those of early stage appeared to be more actively metabolizing and cycling but expressed fewer genes related to immune function. We report differential expression profiles between C-CAFs: early vs. late stage and in the presence of ER antagonists. Both ER antagonists seemed to modulate C-CAF function by down regulating genes associated with cell cycle and metabolism, affecting angiogenesis and cancer progression. This study characterized C-CAFs from early and late stage disease, and experiments with ER inhibitors emphasized the probable importance of canonical ER-α signaling. Interfering with paracrine signaling through fibroblast ER-α is worth exploiting as a targeted therapy in CxCa management.
... In postmenopausal women with advanced BC, letrozole was more effective than fadrozole, a second-generation type Ⅱ nonsteroidal AI with reversible action [54] . The more recent ACOSOG (American College of Surgeons Oncology Group) study compared exemestane, anastrozole, and letrozole as neoadjuvant therapy of women with advanced BC, and reported that the clinical response rate was 62.9%, 69.1%, and 74.8%, respectively [55] .Several meta-analyses underline the aromatase [cytochrome P450 19 (CYP19)], which catalyzes the conversion of androgens, such as testosterone and androstenedione, to estrogens, such as 17-β-estradiol and estrone [44] (Figure 2). ...
Approximately 80% of breast cancers (BC) are estrogen receptor (ER)-positive and thus endocrine therapy (ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of (1) ovarian function suppression (OFS), usually obtained using gonadotropin-releasing hormone agonists (GnRHa); (2) selective estrogen receptor modulators or down-regulators (SERMs or SERDs); and (3) aromatase inhibitors (AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs (i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs (i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type I are permanent steroidal inhibitors of aromatase, while type II are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs (i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors (palbociclib) and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.
... As with CYP2D6 in tamoxifen metabolism, the CYP19A1 gene is the mostly studied pharmacogenomic target associated with AI efficacy and toxicity. Similar to CYP2D6 a number of gene polymorphisms have been described with substantial variation among ethnic groups [24]. The effect of genetic polymorphisms of CYP19A1 on response to AIs has produced conflicting results in studies. ...
Breast cancer is a heterogeneous disease that necessitates proper patient classification to direct surgery, pharmacotherapy, and radiotherapy. Despite patients within the same subgroup receiving similar pharmacotherapy, substantial variation in clinical outcomes is observed. Pharmacogenetic variations with direct effect on pharmacokinetics and pharmacodynamics play a central role in clinical outcomes. Pharmacogenetic markers associated with clinical outcome are known as biomarkers. They are termed prognostic biomarkers when their presence is associated with a specific clinical outcome. If the presence of such biomarkers guides treatment, they are termed predictive biomarkers. A number of pharmacogenetic markers have been described in relation to breast cancer pharmacotherapy both in the adjuvant and neoadjuvant setting. CYP2D6 allelic variants produce variable rates of tamoxifen metabolism and are associated with survival outcomes. Other biomarkers have been described in relation to other forms of endocrine therapy and trastuzumab. In neoadjuvant and adjuvant breast cancer chemotherapy, specific biomarkers were correlated with clinical outcomes and risk of drug toxicity. This review highlights key biomarkers in breast cancer pharmacotherapy with the potential of translating such study outcomes into clinical practice.
... It is expressed especially in the ovaries as well as several extragonadal tissues (subcutaneous fat, brain, liver, bone, vascular endothelial tissues, and the mesenchymal cells of the adipose tissue in the breast) [12]. Ma et al. [13] 'resequenced' all coding exons, all upstream untranslated exons plus their presumed core promoter regions, all exon-intron splice junctions, and a portion of the 3'-untranslated region of CYP19 using 240 DNA samples from patients of four ethnic groups and identified eighty-eight polymorphisms that resulted in 44 haplotypes. Many studies have reported an association between BC risk and the CYP19A1 genotype141516. ...
Many clinical trials have shown the efficacy of aromatase inhibitors (AIs) in the management of breast cancer (BC). There is growing evidence that CYP19A1 single-nucleotide polymorphisms (SNPs) are associated with clinical response (CR) and adverse effects (AEs) among BC patients treated with AIs. The aim of this study was to analyze the association between CYP19A1 polymorphisms and AI treatment in BC patients.
A systematic review was performed in MEDLINE, EMBASE, and LILACS. A meta-analysis was conducted to compare the association between CYP19A1 variants and treatment response among BC patients.
A total of 12 studies were included in the final analysis. There was significant variation among the populations studied and the SNPs and outcomes investigated. A meta-analysis was only possible for the evaluation of SNP rs4646 vs. the wild-type variant with respect to time to progression (TTP) among metastatic BC patients treated with AI. TTP was significantly increased in patients with the rs4646 variant compared with the wild-type gene (hazard ratio (HR) = 0.51 [95 % confidence interval (CI), 0.33-0.78], P = 0.002). Seven studies analyzed the association between AEs with different polymorphisms of CYP19A1. Although there was a statistically significant association with musculoskeletal adverse events (rs934635, rs60271534, rs700518rs, and haplotype M_3_5) and with vasomotor symptoms (rs934635, rs1694189, rs7176005, and haplotype M_5_3) in individual studies, similar associations were not observed in further studies. No statistically significant association between musculoskeletal AEs and SNPs rs4646, rs10046, rs727479, and rs1062033 was found.
These findings suggest that the presence of the rs4646 variant may be a predictive factor of the benefit of AI treatment for BC. The effects of CYP19A1 polymorphisms on clinical outcomes were most often detected in individual studies, suggesting that longer-term studies will better clarify these associations. Additional studies are needed to clarify the predictive value of other SNPs and whether CYP19A1 genotyping should be used to guide AI treatment.
... Obesity, particularly abdominal obesity, is one of the independent factors aggravating the PCOS endocrine disorders, as subcutaneous abdominal adipose tissues and the liver tissues contribute to extragonadal aromatization [5]. Aromatase, a product of the CYP19 gene [6], is a member of the cytochrome P450 family [7]. Aromatase is a rate-limiting enzyme that catalyzes the conversion of androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) during steroidogenesis [8]. ...
Background
This study aimed to investigate the effect of polycystic ovary syndrome (PCOS) on the association of aromatase activity assessed by estradiol-to-testosterone ratio (E2/T) with body mass index (BMI) in women.
Methods
This was a cohort study in five centers for reproductive medicine in China. Data were collected from July 2012 to December 2013. PCOS patients (n = 785) and non PCOS, healthy, age-matched controls (n = 297) were included. Plasma sex hormones including estradiol (E2), testosterone (T), follicle stimulating hormone (FSH), and luteinizing hormone (LH) were measured by ELISA, together with BMI and E2/T being calculated, on the third day of the menstrual cycle. Aromatase activity in PCOS patients with different BMI, T and E2 levels were compared.
Results
E2/T was significantly lower (P < 0.05) while BMI was significantly increased (P < 0.05) in PCOS than non-PCOS. No significant difference was observed in E2/T among different BMI subgroups of either PCOS or control. Ovarian aromatase activity was decreased in PCOS patients which was independent of BMI. Hyperestrogen promoted ovarian aromatase activity, while hyperandrogen inhibited such activity, both in a dose-dependent, biphasic manner.
Conclusions
Ovarian aromatase activity was lower in PCOS, which was independent of BMI. New therapeutic strategies can be developed by targeting aromatase activity for treating PCOS women, especially those with obesity.
... Genetic polymorphisms in CYP19A1 gene correlate with the activity of aromatase, sex hormone levels, and estrogen dependent conditions. However, it is unclear what molecular mechanisms are involved [5] [6] [7] [8] [9]. It has been demonstrated that both estrogens and aromatase are produced in vascular tissue, particularly in smooth muscle cells and endothelial cells [10] [11]. ...
The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the biosynthesis of estrogens. The rs10046 polymorphism of CYP19A1 gene has been investigated in two studies on the occurrence of hypertension, but there are no studies on its correlation with coronary artery disease (CAD). We investigated 189 subjects who were hospitalized at “KAT” General Hospital of Athens and underwent coronary angiography. Of these, 123 were found with CAD with an average age of 60 years and constituted the patients group and 66 subjects with an average age of 58 years without damage in the coronary vessels and constituted the control group (healthy). The frequencies of genotypes CC, CT, and TT of rs10046 polymorphism are significantly different between the group of CAD patients and the control group (0.34, 0.48, and 0.18 versus 0.20, 0.48, and 0.32, resp.,
P
=
0.034
) as the frequency of C allele (0.58 versus 0.44, resp., OR = 1.771 and
P
=
0.010
). We found similar results for men, but not for women (small sample). The results of this study show that the rs10046 (C/T) polymorphism of CYP19A1 gene exhibits correlation with CAD and that patients with C allele have an increased probability of manifesting the disease.
... The aromatase cytochrome P450, encoded by the CYP19 gene, is the enzyme responsible for catalyzing the fi nal step of conversion of androgens into estrogens [ 5 , 6 ] . It is a key gene in determining androgen and estrogen levels [ 7 ] . The serum estradiol/ testosterone ratio has been considered as an indirect marker of aromatase activity [ 8 , 9 ] and it could be used to determine if a particular serum testosterone value is due to higher or lower aromatase activity. ...
Men living at high altitudes in Peru compared to sea level counterparts have erythrocytosis (hemoglobin 16-21 g/dl) or excessive erythrocytosis (hemoglobin>21 g/dl). High testosterone (T) levels in men at high altitude (HA) were associated with excessive erythrocytosis. High androgen levels could be due to a low aromatase activity or to an elevated rate of conversion from precursors to testosterone. The aim of this study was to evaluate aromatase activity and rate of conversion from precursors to testosterone before and after administration of the aromatase enzyme inhibitor letrozole (5 mg/day) for a 5-day period to men at HA and at sea level (SL). The response to short term aromatase inhibition was assessed in 30 adult men living at sea level, 31 native men at HA with erythrocytosis (Hb 16-21 g/dl), and 35 men at HA with excessive erythrocytosis (Hb>21 g/dl). Serum hormone levels, estradiol/testosterone, testosterone/androstenedione, and testosterone/dehydroepiandrosterone sulfate (DHEAS) ratios were measured. Men with erythrocytosis had lower basal serum T/androstenedione ratios than men with excessive erythrocytosis at HA and men at sea level. Men at HA with excessive erythrocytosis had higher T/DHEAS ratios than men with erythrocytosis and than those at sea level before and after letrozole administration. After letrozole administration, both groups of men at high altitude (with erythrocytosis or with excessive erythrocytosis) showed lower aromatase activities than those at sea level. In conclusion, higher serum testosterone levels in men with excessive erythrocytosis were associated with an increased rate of conversion from DHEAS to testosterone rather than to a lower aromatase activity.
... In postmenopausal women, aromatase inhibitors are well-tolerated and improve both disease-free and recurrence-free survival [125][126][127]. Similar to CYP2D6, the Cys 264 and Thr 364 variants in aromatase are associated with decreased activity and lower levels of immunoreactive protein, which may contribute to variation among patients in response to aromatase inhibitor therapy [128]. Although directed endocrine therapies provide treatments specific for patients with hormone-receptorpositive breast cancer, factors such as menopausal status and innate genetic variability may alter the effectiveness of treatment. ...
Breast cancer is a heterogeneous disease with a complex etiology that develops from different cellular lineages, progresses along multiple molecular pathways, and demonstrates wide variability in response to treatment. The "standard of care" approach to breast cancer treatment in which all patients receive similar interventions is rapidly being replaced by personalized medicine, based on molecular characteristics of individual patients. Both inherited and somatic genomic variation is providing useful information for customizing treatment regimens for breast cancer to maximize efficacy and minimize adverse side effects. In this article, we review (1) hereditary breast cancer and current use of inherited susceptibility genes in patient management; (2) the potential of newly-identified breast cancer-susceptibility variants for improving risk assessment; (3) advantages and disadvantages of direct-to-consumer testing; (4) molecular characterization of sporadic breast cancer through immunohistochemistry and gene expression profiling and opportunities for personalized prognostics; and (5) pharmacogenomic influences on the effectiveness of current breast cancer treatments. Molecular genomics has the potential to revolutionize clinical practice and improve the lives of women with breast cancer.
... Similarly, preliminary data show that two singlenucleotide polymorphisms (SNPs) of the aromatase (CYP19) gene correlate with an impaired response to AIs [64]. ...
Approximately 70% of breast cancers express the estrogen receptor (ER) and endocrine therapy is the most important component of systemic therapy for hormone-responsive breast cancer. Unfortunately, endocrine-resistant ER-positive disease represents up to one-quarter of all breast cancers and a number of different mechanisms have been implicated in endocrine resistance, either intrinsic, occurring de novo at the initial exposure to endocrine therapies or acquired, occurring after an initial response to therapy. In the present work a number of molecular mechanisms accounting for intrinsic and acquired resistance to hormonal therapies have been reviewed and the most promising strategies to overcome endocrine resistance have been highlighted.
... Sixty DNA samples each from the Coriell Institute Cell Repository (Camden, New Jersey) CA and AA sample sets (HD100AA and HD100CAU) were used to resequence the 5′-FR and exon 1 of COMT. These DNA samples were deposited in the Coriell Institute by the National Institute of General Medical Sciences and have been widely used to perform gene resequencing studies222324. The subjects who donated the samples provided written consent for their DNA to be used for research purposes, and the samples were anonymized. ...
Catechol O-methyltransferase (COMT) is expressed as both soluble (S) and membrane-bound (MB) isoforms, with S-COMT predominantly expressed in the liver. A common nonsynonymous single nucleotide polymorphism (SNP), 472G > A (108/158Val > Met, S/MB), has been associated with variation in levels of COMT enzyme activity and thermal stability. We set out to test the hypothesis that additional COMT polymorphisms might also be associated with phenotypic variation.
We phenotyped 268 liver biopsy samples for S-COMT activity and thermal stability, resequenced a portion of the gene that had not been resequenced earlier, and genotyped DNA from these same samples for 16 COMT polymorphisms.
There was a significant association between the two COMT phenotypes and genotype at the codon 108 SNP. A haplotype-based approach was then used to assess the possible association of other polymorphisms with phenotype. Specifically, the codon 108 SNP explained 20.4% of variance in enzyme activity (P < 10), and 59% of variance in thermal stability (P < 10). Haplotypes that included SNPs at cDNA nucleotides 408 and 472 explained additional variance in enzyme activity (up to 24.4%), and the addition to the haplotype of a SNP at intron 2 (51) explained a total of 27.5% of the variance. However, no SNPs beyond that at the nucleotide 472G > A polymorphism were associated with variation in thermal stability. We also observed a three-fold variation in the ability of reporter gene constructs for 'proximal promoter' haplotypes to drive transcription.
The common COMT 108Val > Met polymorphism is associated with human liver S-COMT activity and thermal stability, but additional COMT SNPs also contribute to variation in activity.
... Research into pharmacogenetic differences with the AIs is at an earlier stage than with tamoxifen. However, Ma and colleagues [27] sequenced the aromatase gene in 60 patients from each of four ethnic groups (Caucasian-Americans, African-Americans, Han Chinese-Americans and Mexican-Americans) and identified 88 polymorphisms resulting in 44 haplotypes. ...
The clinician caring for women with early breast cancer is keenly aware of the variability observed when endocrine therapy with tamoxifen or the aromatase inhibitors (AIs) is employed. This is seen in outcomes of the disease in terms of recurrence but also, strikingly in some cases, in terms of adverse events. This can be seen in the case of AIs, in which some women develop disabling musculoskeletal events that result in their discontinuing therapy, whereas the majority develops no such adverse events. The same is true of other adverse events such as deep venous thrombosis, endometrial cancer and hot flashes in the case of tamoxifen. In the past, the focus in selection of therapy for women with breast cancer has been almost exclusively on the characteristics of the tumour (for example, oestrogen receptor [ER] and human epidermal growth factor receptor [HER]-2), with essentially no attention given to the genetic make-up of the patient.
Pharmacogenetics and pharmacogenomics involve the study of the role played by inheritance in individual variation in drug response phenotypes such as disease outcomes and end organ effects, including adverse events. These terms are often used interchangeably but, strictly speaking, pharmacogenetics refers to the study of a gene or a number of genes, such as those involved with a pathway, whereas pharmacogenomics involves the entire genome. We have truly entered the era of pharmacogenomics with the introduction of genome-wide association studies (GWASs). Pharmacogenetics/pharmacogenomics have the clinical goals of better selecting responsive patients, maximizing drug efficacy and minimizing adverse reactions. Pharmacokinetics considers factors such as metabolism and transport that influence drug concentrations at the target(s), whereas pharmacodynamics considers factors that influence the response of the target(s), for example receptors, enzymes, transporters and downstream signalling molecules, to the drug.
Endocrine therapy represents the most important therapeutic modality for those women whose tumours are potentially endocrine sensitive, as indicated by expression of the ER and/or progesterone receptor. The selective ER modulator tamoxifen has been the most important therapeutic agent in breast cancer for the past three decades. Tamoxifen has received approval from the US Food and Drug Administration for the full spectrum of breast cancer from metastatic disease to those women who are at higher risk for developing breast cancer. In addition, tamoxifen has received approval for treatment of men with metastatic breast cancer and is commonly used in the adjuvant setting. During the past decade the third generation AIs anastrozole, exemestane and letrozole have emerged as important additions to the clinician's armamentarium against breast cancer. They appear to be more efficacious than tamoxifen in the advanced disease setting [1], have become clearly established in the adjuvant setting [2] and are a major focus of ongoing trials in the prevention setting in postmenopausal women [3]. Tamoxifen and the AIs have recently become foci of intense pharmacogenetic/pharmacogenomic research [4].
... In present study, we performed both SNP-based analyses and haplotype analyses to assess the association of CYP19 gene with adult height. Recently, Ma et al. (2005) identified genetic polymorphisms in CYP19 by resequencing the exons, exon-intron splice junctions, and a portion of the 3′-untranslated regions. Most of the polymorphisms they observed had not been reported previously thus were not analyzed in the present study. ...
Human height is a complex trait regulated by multiple genetic and environmental factors. CYP19 (cytochrome P450 19) encodes aromatase, which catalyses the rate-limiting step in the conversion of androgens to estrogens. Deleterious mutations in CYP19 can result in estrogen deficiency that will influence adult height to certain extent. In the present study, we aimed to test the associations between the CYP19 gene polymorphisms with adult height variation, using family-based association methods, such as QTDT (quantitative transmission disequilibrium test) and FBAT (family-based association test) in 1,873 subjects from 405 Caucasian nuclear families. We found one SNP (rs730154) significantly associated with height by both QTDT (P=0.0030) and FBAT (P=0.0016) analyses. Haplotype analyses corroborated our single-marker results by showing that the haplotypes in block 4 containing rs730154 were significantly associated with height variation. We thus concluded that CYP19 could be one of the genetic factors influencing adult height in Caucasians. Further studies are required to identify the causal functional variants responsible for Caucasian height within the CYP19 gene.
... In a recent study, Ma et al. identified and characterized genetic polymorphisms in the human aromatase gene [18]. There are four single nucleotide polymorphisms (SNPs) in the coding region. ...
Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. In contrast to tamoxifen, an antagonist of the estrogen receptor (ER), AIs have shown to be better tolerated along with decreased recurrence rates of the disease. Currently, three third-generation AIs are being used: exemestane, letrozole, and anastrozole. Our laboratory is attempting to understand several aspects of AI functionality. In this paper, we first review recent findings from our structure-function studies of aromatase as well as the molecular characterization of the interaction between AIs and aromatase. Based on these studies, we propose new evidence for the interaction of letrozole and exemestane with aromatase. In addition, we will discuss recent results generated from our AI-resistant cell lines. Our laboratory has generated MCF-7aro cells that are resistant to letrozole, anastrozole, exemestane, and tamoxifen. Basic functional characterization of aromatase and ERalpha in these resistant cell lines has been done and microarray analysis has been employed in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. The results generated so far suggest the presence of at least four types of resistant cell lines. Overall, the information presented in this paper supplements our understanding of AI function, and such information can be valuable for the development of treatment strategies against AI resistant breast cancers.
... A case-control study found that the CYP19 115T>C (Trp39Arg) polymorphism is significantly associated with breast cancer risk, in that this risk is significantly lower in carriers of the variant Arg (C) allele than in noncarriers in premenopausal Japanese women (Miyoshi et al. 2000;Hirose et al. 2004). Functional genomic studies performed with the Trp39Arg variant and the double variant Arg39-Cys264 revealed a slight decrease in both the activity and quantity of allozyme protein for the Arg (C) allele, whereas double variant Arg39Cys264 allozymes showed significant decreases in the activity and levels of immunoreactive protein when compared with the wild-type enzyme (Ma et al. 2005). The presence of Trp39Arg in a Japanese population resulted in a less active aromatase protein (Miyoshi et al. 2000;Nativelle-Serpentini et al. 2002). ...
A variety of factors affect the development of endometriosis, including hormonal status and genetic factors. The growth of endometriosis is stimulated by local estrogen production in conjunction with circulating estrogen. The CYP19 gene encodes a steroid aromatase that catalyses the conversion of C-19 androgens to estrogens. This study investigated whether polymorphisms of the CYP19 gene are associated with the risk of advanced endometriosis in Korean women. Blood samples were collected from 224 female patients with endometriosis of stages III and IV, as diagnosed by both pathologic and laparoscopic findings, and from a control group comprising of 188 women undergoing laparoscopic surgery or laparotomy for nonmalignant lesions. Single-nucleotide polymorphisms, restriction fragment length polymorphisms, and tetranucleotide tandem repeat polymorphisms were discriminated by the polymerase chain reaction (PCR). Haplotype analysis was also performed. CYP19 115T>C, 240G>A, and 1531C>T polymorphisms and [TTTA]n tetranucleotide repeat polymorphisms in the CYP19 gene and their haplotypes were not significantly associated with the risk of endometriosis. The risk of endometriosis also did not increase significantly with the number of higher risk alleles of the CYP19 gene. In conclusion, our findings suggest that CYP19 genetic polymorphisms are not associated with advanced-stage endometriosis in Korean women.
... 10,11 Thus, genetic variations in CYP19A1, the gene encoding aromatase, might contribute to alterations in aromatase expression and enzyme activity, which are related to the estrogens/androgens balance. 12 We and other researchers have recently shown that common polymorphisms of the aromatase gene (rs11575899 and rs10046) are associated with estradiol and androgen serum levels in premeopausal and postmenopausal women. [13][14][15][16] Furthermore, it has been reported that the effect of these genetic variants of CYP19A1 gene are dependent of body fat accumulation in women. ...
Sexual dimorphism in blood pressure (BP) regulation has been observed both in humans and experimental animals, and estrogens have been shown to contribute to this epidemiological observation. A key enzyme in determining estrogen levels is aromatase cytochrome P450. The aim of this study was to evaluate the role of the gene encoding aromatase, CYP19A1, as an independent risk factor for hypertension and its relationship with systolic and diastolic BP measures. We genotyped 2 polymorphisms within the CYP19A1 gene, IVS4 rs11575899 and 3'UTR rs10046, in 3448 individuals. In quantitative analysis, we observed significant associations between the 2 polymorphisms and BP values in women, being these associations dependent on BMI and independent of menopause status. The case-control analysis revealed that the most prominent associations were found for nonobese women in diastolic hypertension (DHT): the IVS4_22 and 3'UTR_11 are risk genotypes (OR=1.61, P=0.027 and OR=1.59, P=0.012, respectively), whereas IVS4_11 and 3'UTR_22 genotypes have a protective effect against DHT (OR=0.63, P=0.009, and OR=0.61, P=0.020, respectively). Haplotype analysis confirmed the above associations: among nonobese women the haplotype 21 is overrepresented in hypertensive women (OR=1.33, P=0.004, for DHT and OR=1.25, P=0.026, for systolic hypertension, SHT) and, conversely, the haplotype 12 protects against hypertension (OR=0.78, P=0.015 for DHT and OR=0.82, P=0.04 for SHT). Our study has shown that the CYP19A1 gene may be involved in the genetic regulation of BP in women. This effect is dependent on BMI and independent of menopause status, suggesting that this action is mainly driven by aromatase activity in fat tissue.
... Moreover, estrogen concentrations are higher in tumors than in surrounding non-malignant tissue [41,[54][55][56][57][58]. Recent research has increased understanding of how aromatase is regulated by tissue-specific promoters [59] and how genetic variation may affect the pathophysiology of estrogendependent disease [60]. Pharmacogenomics may become an increasingly important tool for individualizing hormonal therapy for patients with breast cancer. ...
Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole (Femara) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women.
Background
Different genetic variants in hormone-regulating pathways have been identified to influence the risk of breast cancer. This study aimed to evaluate the association of CYP19A1 rs10046 and rs700519 polymorphisms with the risk, clinicopathological factors and prognosis of breast cancer.
Methods
In a case-control study, rs10046 and rs700519 polymorphisms were genotyped using ARMS-PCR and high-resolution melting (HRM), respectively, in a total of 702 females. Statistical analysis and evaluation of haplotypes and linkage disequilibrium were performed using SPSS v16, PHASE and 2LD.
Results
Although no association of rs700519 with breast cancer was observed, rs10046 in different genetic models as well as C-C/C-T and C-C/C-C diplotypes, revealed the association with the risk of breast cancer (p < 0.05). Moreover, the rs700519-C allele was shown to be associated with longer overall survival. In contrast, the T-T haplotype conferred s a shorter overall survival. rs700519-C allele was also significantly associated with menarche age.
Conclusion
Based on the identified independent association between CYP19A1 diplotypes and rs700519-C allele with the risk and prognosis of the disease, the gene region and its genetic variants may have a diagnostic and prognostic role in breast cancer development. Further confirmation using other variants in this locus can validate these findings.
Background:
Melanoma is the leading cause of death from skin cancers and its etiology is complex. Recent discoveries related to genetic risk factors are helping us to understand melanoma pathogenesis better. Nuclear factor-κB (NF-κB) has a critical role in immunity, inflammation, and tumor growth. The 94ins/del ATTG (rs28362491) polymorphism located in the NFKB1 gene has been associated to various cancers and the ATTG2/ATTG2 genotype was correlated to melanoma risk in Sweden. The CYP19A1 gene encodes the enzyme aromatase, which is active in malignant melanoma tissue. In addition, the CYP19A1 TCT insertion/deletion variant in intron 4 (rs11575899) has been associated with an increased incidence of cancer, albeit with conflicting results. The goal of this study was to investigate possible associations between these two gene variants and melanoma.
Methods:
In this case-control study, we evaluated 117 cutaneous melanoma patients and 116 controls from southern Brazil. Genotyping of rs28362491 and rs11575899 was carried out by means of PCR amplification and capillary electrophoresis. Logistic regression was used to obtain odds ratios (ORs) of melanoma, according to genotypes.
Results:
We identified an association between the ATTG2/ATTG2 and melanoma [OR=1.78; 95% confidence interval (CI): 1.06-3.00; P=0.03]. In addition, there was a dose effect: for each ins allele in the genotype, the risk for melanoma increased (OR=1.51; 95% CI: 1.08-2.11; P=0.017). As regards the CYP19A1 variant, genotype 11 (del/del) was more frequent in patients than in controls (OR=1.85; 95% CI 1.06-3.22; P=0.03).
Conclusion:
The NFKB1 ATTG2/ATTG2 and CYP19A1 del/del genotypes are significantly associated with melanoma and could be genetic markers of melanoma susceptibility in southern Brazilian population.
So far, no reliable predictive clinicopathological markers of response to aromatase inhibitors (AIs) have been identified, and little is known regarding the role played by host genetics. To identify constitutive predictive markers, an array-based association study was performed in a cohort of 55 elderly hormone-dependent breast cancer (BC) patients treated with third-generation AIs. The array used in this study interrogates variants in 225 drug metabolism and disposition genes with documented functional significance. Six variants emerged as associated with response to AIs: three located in ABCG1, UGT2A1, SLCO3A1 with a good response, two in SLCO3A1 and one in ABCC4 with a poor response. Variants in the AI target CYP19A1 resulted associated with a favourable response only as haplotype; haplotypes with increased response association were also detected for ABCG1 and SLCO3A1. These results highlight the relevance of host genetics in the response to AIs and represent a first step toward precision medicine for elderly BC patients.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.73.
Purpose:
Aromatase, encoded by the CYP19 gene, catalyzes the final step of the conversion of androgens to estrogens. Given the critical role of CYP19 in estrogen synthesis, the potential influence of CYP19 rs4646 polymorphism on breast cancer survival, deserves further study.
Methods:
Genotyping for CYP19 rs4646 variants was performed on 406 Chinese women with stage I-II and operable stage III breast cancer. Associations were evaluated between CYP19 rs4646 genotypes and disease-free survival (DFS).
Results:
In premenopausal patients, women who are homozygous for the minor allele (AA) have a longer DFS compared with those carrying the major allele (CC or AC) (87 months versus 48.7 months; Hazard ratio (HR) = 0.56, 95 % CI = 0.318-0.985, P = 0.041). These differences were further demonstrated by a multivariate analysis (HR = 0.456, 95 % CI = 0.249-0.836, P = 0.011). Conversely, the same variant (AA) was estimated to be associated with a poorer DFS in postmenopausal women (AA versus AC or CC: 13.7 months versus 56.3 months; HR = 2.758, 95 % CI = 1.432-5.313, P = 0.002). Furthermore, the differences were confirmed by the COX proportional hazards model (HR = 2.983, 95% CI =1.494-5.955, P = 0.002).
Conclusions:
The present study indicates that CYP19 rs4646 polymorphism is related to DFS in early breast cancer and that the prognosis index of the homozygous for the minor allele (AA) may depend on menopause status. The findings are novel, if confirmed, rs4646 genotypes may provide useful information for routine management in breast cancer.
Given the critical role of CYP19 in estrogen synthesis, we investigated the influence of CYP19 gene polymorphisms on the clinical outcome of lymph node- (LN-) negative, hormone receptor- (HR-) positive early breast cancers. Genotyping for the CYP19 polymorphisms rs4646 (A/C), rs1065779 (A/C), CYP19 (TTTA)n (short allele/long (S/L) allele using the 7 TTTA repeat polymorphism as the cut-off), and rs1870050 (A/C) was performed on 296 patients with LN-negative, HR-positive breast cancers. All patients received adjuvant hormonal therapy. Associations were examined between these 4 genotypes and 6 common haplotypes of CYP19 and distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Patients were divided into the 6 subhaplotypes of CCLA (41.1%), AASA (17.1%), CASA (11.9%), CCLC (8.9%), CCSA (7.5%), AASC (8.9%), and others (4.6%). In premenopausal patients, haplotype AASA was significantly associated with a poor DDFS (adjusted hazard ratio (aHR), 3.3; P = 0.001), DFS (aHR, 2.5; P = 0.0008), and OS (aHR, 2.9; P = 0.0004) after adjusting for age, tumor size, tumor grade, estrogen receptor status, progesterone receptor status, chemotherapy, pathology, adjuvant hormone therapy, menopausal status, and radiotherapy. Furthermore, haplotype AASA remained a negative prognostic factor for premenopausal patients receiving adjuvant chemotherapy in terms of DDFS (aHR, 4.5; P = 0.0005), DFS (HR, 3.2; P = 0.003), and OS (HR, 6.4; P = 0.0009). However, in postmenopausal patients, haplotype AASA was not associated with a poor prognosis, whereas the AASC haplotype was significantly associated with a poor DFS (aHR, 3.1; P = 0.03) and OS (aHR, 4.4; P = 0.01). Our results indicate that, in patients with LN-negative, HR-positive breast cancers, genetic polymorphism haplotype AASA is associated with poor survival of premenopausal women but does not affect survival of postmenopausal women.
The most important modality of treatment in the two-thirds of patients with an estrogen receptor (ER)-positive early breast cancer is endocrine therapy. In postmenopausal women, options include the selective ER modulators (SERMs), tamoxifen and raloxifene, and the 'third-generation' aromatase inhibitors (AIs), anastrozole, exemestane and letrozole. Under the auspices of the National Institutes of Health Global Alliance for Pharmacogenomics, Japan, the Mayo Clinic Pharmacogenomics Research Network Center and the RIKEN Center for Genomic Medicine have worked collaboratively to perform genome-wide association studies (GWAS) in women treated with both SERMs and AIs. On the basis of the results of the GWAS, scientists at the Mayo Clinic have proceeded with functional genomic laboratory studies. As will be seen in this review, this has led to new knowledge relating to endocrine biology that has provided a clear focus for further research to move toward truly personalized medicine for women with breast cancer.Journal of Human Genetics advance online publication, 2 May 2013; doi:10.1038/jhg.2013.35.
Although normal breast tissue and breast cancer estrogens are known to be elevated compared with plasma estrogen levels, the mechanism behind this phenomenon has been an issue of debate for 2 decades. If local estrogen aromatization were to be confirmed as the main estrogen source in breast cancer tissue, tissue-specific inhibition of estrogen production, avoiding systemic side effects, would become a potentially attractive option for breast cancer treatment and prevention. Based on recent results from our groups exploring tissue estrogens, together with estrogen-synthesizing and estrogen-regulated gene expression levels, we propose a new model to explain elevated breast tissue estrogen levels. Although local estrogen production may be important, the local contribution is overruled by rapid plasma-to-tissue equilibration, including active uptake of circulating estrogens or enhanced tissue binding. As for breast cancer tissue levels, elevated levels of estradiol may be explained to a large extent by estrogen receptor binding and local conversion of estrone into estradiol. This model indicates that effective suppression of benign and malignant tissue estrogens as a treatment for ER+ breast cancer requires systemic suppression and will not be markedly affected by local enzyme targeting.
CYP19A1 encodes aromatase, the enzyme responsible for the conversion of androgens to estrogens, and may play a role in variation in outcomes among men and women with cardiovascular disease. We sought to examine genetic variation in CYP19A1 for its potential role in sex differences in cardiovascular disease outcomes.
Caucasian individuals from two independent populations were assessed: 1) a prospective cohort of patients with acute coronary syndromes with 3-year mortality follow-up (n = 568) and 2) a nested case-control study from a randomized, controlled trial of hypertension patients with stable coronary disease in which the primary outcome was death, nonfatal myocardial infarction (MI) or nonfatal stroke (n = 619). Six CYP19A1 SNPs were genotyped (-81371 C>T, -45965 G>C, M201T, R264C, 80 A>G, and +32226 G>A). The sex*genotype interaction term was assessed for the primary outcome and compared by genotype in men and women when a significant interaction term was identified.
We identified a significant interaction between -81371 C>T and sex (p = 0.025) in the ACS population. The variant allele was associated with a 78% increase in mortality in men (HR 1.78, 95% confidence interval [CI] 1.08-2.94) and a nonsignificant 42% decrease in mortality among women (HR 0.58, 95% CI 0.22-1.54). We identified a similar association in the hypertensive CAD group, the -81371 C>T*sex interaction term was p<0.0001, with an associated 65% increase in death, MI, or stroke (HR 1.65, 95% CI 1.00-2.73) in men and a 69% decrease (HR 0.31, 95% CI 0.16-0.6) in women.
Using two independent populations, this study is the first to document a significant interaction between CYP19A1 genotype and sex on cardiovascular outcomes. These findings could illuminate potential mechanisms of sex differences in cardiovascular disease outcomes.
Safety factors are used in ecological risk assessments to extrapolate from the toxic responses of laboratory test species to all species representing that group in the environment. More accurate extrapolation of species responses is important. Advances in understanding the mechanistic basis for toxicological responses and identifying molecular response pathways can provide a basis for extrapolation across species and, in part, an explanation for the variability in whole organism responses to toxicants. We highlight potential short- and medium-term development goals to meet our long-term aspiration of truly predictive in silico extrapolation across wildlife species' response to toxicants. A conceptual approach for considering cross-species extrapolation is presented. Critical information is required to establish evidence-based species extrapolation, including identification of critical molecular pathways and regulatory networks that are linked to the biological mode of action and species' homologies. A case study is presented that examines steroidogenesis inhibition in fish after exposure to fadrozole or prochloraz. Similar effects for each compound among fathead minnow, medaka, and zebrafish were attributed to similar inhibitor pharmacokinetic/pharmacodynamic distributions and sequences of cytochrome P45019A1/2 (CYP19A1/2). Rapid advances in homology modeling allow the prediction of interactions of chemicals with enzymes, for example, CYP19 aromatase, which would eventually allow a prediction of potential aromatase toxicity of new compounds across a range of species. Eventually, predictive models will be developed to extrapolate across species, although substantial research is still required. Knowledge gaps requiring research include defining differences in life histories (e.g., reproductive strategies), understanding tissue-specific gene expression, and defining the role of metabolism on toxic responses and how these collectively affect the power of interspecies extrapolation methods.
During testosterone (T) therapy, T is partly converted to 17beta-estradiol (E2) and 5alpha-dihydrotestosterone (DHT). Effects of age, testosterone dose, and body composition on total and free E2 and DHT levels are unknown.
We evaluated age and dose-related differences in E2 and DHT levels in response to graded doses of testosterone enanthate in young and older men.
Fifty-one young (aged 19-35 yr) and 52 older (aged 59-75 yr) men completed treatment with monthly injections of a GnRH agonist plus randomly assigned weekly doses of testosterone enanthate (25, 50, 125, 300, or 600 mg) for 5 months.
During testosterone administration, total and free E2 levels increased dose-dependently (dose effect, P<0.001) in both young and older men. Total and free E2 levels and E2:T ratios during T administration were higher in older than young men, but age-related differences in free E2 and free E2:T ratios were not significant after adjusting for testosterone levels, percentage fat mass, and SHBG. DHT levels and DHT:T ratios were dose-related but did not differ between young and older men. Mechanistic modeling of free hormone data revealed that the conversions of T to E2 and DHT were both consistent with saturable Michaelis-Menten kinetics. The in vivo Km values were estimated to be 1.83 nm for aromatase and 3.35 nm for 5alpha-reductase, independent of age. The Vmax parameter for E2 was 40% higher in older men than younger men, but Vmax for DHT was not significantly different between age groups.
During im testosterone administration, E2 and DHT levels exhibit saturable increases with dose. The rate of whole body aromatization is higher in older men, partly related to their higher percentage fat mass, SHBG, and testosterone levels.
Aims and background:
Approximately half of metastatic breast cancers expressing estrogen and/or progesterone receptors responds to endocrine therapy, and postoperative adjuvant endocrine therapy provides about a 50% reduction in the development of recurrent disease. A number of publications have focused on the correlation of biomarkers, in particular estrogen and progesterone receptors and HER-2/neu status as well as different gene profiles, multigene assays and genetic polymorphisms with response to hormone therapy. The purpose of this article is to review the literature to identify biological markers predictive of response to tamoxifen and aromatase inhibitors.
Methods:
A computerized literature search through Medline and ASCO abstract databases was performed, applying the words "endocrine therapy" and "predictive markers" and each of the following: early and metastatic breast cancer, estrogen receptors, progesterone receptors, HER2/neu, multigene assays, polymorphisms. The last search was updated in June 2007. In the examined literature, biological markers were retrospectively assayed to establish whether such variables were predictive for endocrine therapy efficacy.
Results:
The role of estrogen receptor content as a predictor of response to endocrine treatment was confirmed: benefit from endocrine treatment was directly proportional to estrogen receptor levels. Progesterone receptor status was only a strong time-dependent prognostic value, and it has not yet been validated as a predictive factor of tamoxifen efficacy. Retrospective clinical data from upfront and sequential studies of aromatase inhibitors were discordant regarding the degree of benefit of these drugs over tamoxifen according to progesterone receptor status. HER-2 positivity was associated with a significantly greater risk of endocrine therapy failure in metastatic and neoadjuvant settings. The current generation of genomic assays for tamoxifen sensitivity all contain a combination of prognostic information that it is difficult to integrate into clinical practice.
Conclusions:
Available clinical data are inconclusive to support preferential use of aromatase inhibitors over tamoxifen in progesterone-receptor-negative and HER-2-positive tumors, but it was also clear that lower estrogen receptors, lower progesterone receptors, and positive HER-2 are associated with lower responsiveness to any type of endocrine therapy. Tumors overexpressing HER-2 are endocrine resistant and they require the blockage of the HER-2 pathway in addition to estrogen deprivation. Recent molecular studies have shown that endocrine responsiveness is to a large extent influenced by estrogen-receptor-related pathways. In the future, the key to the correct tailoring of hormone therapy will probably be the ability to subtype estrogen-receptor-positive breast cancer.
Third-generation nonsteroidal aromatase inhibitors (AIs), letrozole and anastrozole, are superior to tamoxifen as initial therapy for early breast cancer but have not been directly compared in a head-to-head adjuvant trial. Cumulative evidence suggests that AIs are not equivalent in terms of potency of estrogen suppression and that there may be differences in clinical efficacy. Thus, with no data from head-to-head comparisons of the AIs as adjuvant therapy yet available, the question of whether there are efficacy differences between the AIs remains. To help answer this question, the Femara versus Anastrozole Clinical Evaluation (FACE) is a phase IIIb open-label, randomized, multicenter trial designed to test whether letrozole or anastrozole has superior efficacy as adjuvant treatment of postmenopausal women with hormone receptor (HR)- and lymph node-positive breast cancer. Eligible patients (target accrual, N=4,000) are randomized to receive either letrozole 2.5 mg or anastrozole 1 mg daily for up to 5 years. The primary objective is to compare disease-free survival at 5 years. Secondary end points include safety, overall survival, time to distant metastases, and time to contralateral breast cancer. The FACE trial will determine whether or not letrozole offers a greater clinical benefit to postmenopausal women with HR+ early breast cancer at increased risk of early recurrence compared with anastrozole.
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