Charles E Wood

Wake Forest School of Medicine, Wake Forest, NC, United States

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Publications (39)160.37 Total impact

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    ABSTRACT: The estrogen analog tamoxifen (TAM), used for adjuvant therapy of breast cancer, induces endometrial and uterine tumors in breast cancer patients. Proliferation stimulus of the uterine endometrium is likely involved in tumor induction, but genotoxicity may also play a role. Formation of TAM-DNA adducts in human tissues has been reported but remains controversial. To address this issue, we examined TAM-DNA adducts in uteri from two species of monkeys, Erythrocebus patas (patas) and Macaca fascicularis (macaque) and in human endometrium and myometrium. Monkeys were given 3-4 months of chronic TAM dosing scaled to be equivalent to the daily human dose. In the uteri, livers and brains from the patas (n=3), and endometrium from the macaques (n=4), TAM-DNA adducts were measurable by TAM-DNA Chemiluminescence Immunoassay (CIA). Average TAM-DNA adduct values for the patas uteri (23 adducts/10(8) nucleotides) were similar to those found in endometrium of the macaques (19 adducts/10(8) nucleotides). Endometrium of macaques exposed to both TAM and low-dose estradiol (n=5) averaged 34 adducts/10(8) nucleotides. To examine TAM-DNA persistence in the patas, females (n=3) were exposed to TAM for 3 months and to no drug for an additional month, resulting in low or non-detectable TAM-DNA in livers and uteri. Human endometrial and myometrial samples from women receiving (n=8) and not receiving (n=8) TAM therapy were also evaluated. Women receiving TAM therapy averaged 10.3 TAM-DNA adducts/10(8) nucleotides, while unexposed women showed no detectable TAM-DNA. The data indicate that genotoxicity, in addition to estrogen-agonist effects, may contribute to TAM-induced human endometrial cancer.
    Carcinogenesis 02/2014; · 5.64 Impact Factor
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    ABSTRACT: Menopausal hormone therapies vary widely in their effects on breast cancer risk, and the mechanisms underlying these differences are unclear. The primary goals of this study were to characterize the mammary gland transcriptional profile of estrogen+progestin therapy in comparison with estrogen-alone or tibolone and investigate pathways of cell proliferation in a postmenopausal primate model. Ovariectomized female cynomolgus macaque monkeys were randomized into the following groups: placebo (Con), oral conjugated equine estrogens (CEE), CEE with medroxyprogesterone acetate (MPA) (CEE+MPA), and tibolone given at a low or high dose (Lo or Hi Tib). All study treatment doses represented human clinical dose equivalents and were administered in the diet over a period of 2 years. Treatment with CEE+MPA had the greatest effect on global mRNA profiles and markers of mammary gland proliferation compared to CEE or tibolone treatment. Changes in the transcriptional patterns resulting from the addition of MPA to CEE were related to increased growth factors and decreased estrogen receptor (ER) signaling. Specific genes induced by CEE+MPA treatment included key members of prolactin receptor (PRLR)/signal transducer and activator of transcription 5 (STAT5), epidermal growth factor receptor (EGFR), and receptor activator of nuclear factor kappa B (RANK)/receptor activator of nuclear factor kappa B ligand (RANKL) pathways that were highly associated with breast tissue proliferation. In contrast, tibolone did not affect breast tissue proliferation but did elicit a mixed pattern of ER agonist activity. Our findings indicate that estrogen+progestin therapy results in a distinct molecular profile compared to estrogen-alone or tibolone therapy, including upregulation of key growth factor targets associated with mammary carcinogenesis in mouse models. These changes may contribute to the promotional effects of estrogen+progestin therapy on breast cancer risk.
    Breast cancer research: BCR 08/2013; 15(4):R62. · 5.87 Impact Factor
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    ABSTRACT: Concerns of breast cancer risk in postmenopausal women taking combined estrogen + progestin therapy have generated interest in the use of selective estrogen receptor modulators (SERMs) as potential progestin alternatives. Endometrial proliferation and cancer risk are major concerns, however, for estrogens and certain types of SERMs when given alone. The primary aim of this study was to evaluate the endometrial profile of bazedoxifene acetate (BZA), a third-generation SERM, alone and in combination with conjugated equine estrogens (CEE) in a postmenopausal primate model. Ninety-eight ovariectomized cynomolgus monkeys (Macaca fascicularis) were randomized to receive no hormone treatment (controls), BZA 20 mg, CEE 0.45 mg, or the combination of BZA 20 mg + CEE 0.45 mg once daily for 20 months in a parallel-arm study design. The primary outcome measure was endometrial epithelial proliferation. BZA + CEE and BZA treatment resulted in significantly less endometrial epithelial area and Ki67 expression compared with CEE (P < 0.001 for all). The prevalence of endometrial hyperplasia and other estrogen-induced morphologic changes in the BZA + CEE and BZA groups was not significantly different from controls. The addition of BZA to CEE completely inhibited the expression of estrogen receptor-α-regulated genes (TFF1 and PGR), whereas BZA alone had no effect. BZA + CEE and BZA treatment also resulted in lower estrogen receptor-α protein expression in the endometrium compared with the control and CEE groups (P < 0.05 for all). BZA given at a clinically relevant dose inhibits estrogen effects on the endometrium and lacks uterotropic effects when given alone.
    Menopause (New York, N.Y.) 07/2013; 20(7):777-84. · 3.08 Impact Factor
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    ABSTRACT: While epidemiologic studies suggest that soy intake early in life may reduce breast cancer risk, there are also concerns that exposure to soy isoflavones during childhood may alter pubertal development and hormonal profiles. Here, we assessed the effect of a high-soy diet on pubertal breast development, sex hormones, and growth in a nonhuman primate model. Pubertal female cynomolgus monkeys were randomized to receive a diet modeled on a typical North American diet with one of two protein sources for ~4.5 years: i) casein/lactalbumin (CL, n=12, as control) or ii) soy protein isolate with a human equivalent dose of 120 mg/day isoflavones (SOY, n=17), which is comparable to approximately four servings of soy foods. Pubertal exposure to the SOY diet did not alter onset of menarche, indicators of growth and pubertal progression, or circulating estradiol and progesterone concentrations. Greater endometrial area was seen in the SOY group on the first of 4 postmenarchal ultrasound measurements (P<0.05). There was a subtle effect of diet on breast differentiation whereby the SOY group showed higher numbers of differentiated large-sized lobular units and a lower proportion with immature ducts following menarche (P<0.05). Numbers of small lobules and terminal end buds and mammary epithelial cell proliferation did not differ by diet. Expression of progesterone receptor was lower in immature lobules of soy-fed animals (P<0.05). Our findings suggest that consumption of soy starting before menarche may result in modest effects consistent with a more differentiated breast phenotype in adulthood.
    Cancer Prevention Research 06/2013; · 4.89 Impact Factor
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    ABSTRACT: Genital condyloma-like lesions were observed on male and female cynomolgus macaque monkeys (Macaca fascicularis) originating from the island of Mauritius. Cytobrush and/or biopsy samples were obtained from lesions of 57 affected macaques. Primary histologic features included eosinophilic, neutrophilic, and lymphoplasmacytic penile and vulvar inflammation, epidermal hyperplasia with acanthosis, and increased collagenous stroma. Polymerase chain reaction-based assays to amplify viral DNA revealed the presence of macaque lymphocryptovirus (LCV) DNA but not papillomavirus or poxvirus DNA. Subsequent DNA analyses of 3 genomic regions of LCV identified isolates associated with lesions in 19/25 (76%) biopsies and 19/57 (33%) cytology samples. Variable immunolabeling for proteins related to the human LCV Epstein Barr Virus was observed within intralesional plasma cells, stromal cells, and epithelial cells. Further work is needed to characterize the epidemiologic features of these lesions and their association with LCV infection in Mauritian-origin macaques.
    Toxicologic Pathology 12/2012; · 2.06 Impact Factor
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    ABSTRACT: Concerns about increased breast cancer risk with estrogen and progestin therapy have led to an increased interest in progestin alternatives. The main objective of this study was to determine if bazedoxifene acetate (BZA), a new selective estrogen receptor modulator, will antagonize the proliferative and transcriptional effects of conjugated equine estrogens (CEE) in the breast. As part of a 20-month preclinical trial, 95 ovariectomized cynomolgus macaques (Macaca fascicularis) were randomized to receive no treatment or treatment with BZA (20 mg/d), CEE (0.45 mg/d), or BZA and CEE in combination (women's daily equivalent doses). The data presented here include breast effects after 6 months of treatment. Endpoints included histomorphometry, histopathological evaluations, gene microarray assays, polymerase chain reaction quantification of specific estrogen receptor α (ER-α) activity markers, and immunohistochemical detection of sex steroid receptors, and the proliferation marker Ki67. BZA + CEE and BZA resulted in significantly less total epithelial density, lobular enlargement, and Ki67 immunolabeling in the terminal ducts compared with CEE alone (P < 0.05 for all). The addition of BZA to CEE antagonized the expression of ER-α-regulated genes such as GREB1 and TFF1 (P < 0.01 for both), whereas BZA alone had minimal effects on ER-α-mediated transcriptional activity. BZA and BZA + CEE did not significantly up-regulate genes related to cell cycle progression and proliferation. BZA with and without CEE also resulted in less lobular and terminal duct ER-α immunolabeling compared with control and CEE (P < 0.0001 for all). These findings demonstrate that BZA given at a clinically relevant dose is an estrogen antagonist in the breast, supporting the idea that CEE + BZA may provide a lower breast cancer risk profile compared with traditional estrogen + progestin therapies.
    Menopause (New York, N.Y.) 11/2012; 19(11):1242-52. · 3.08 Impact Factor
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    ABSTRACT: Equol is an isoflavone (IF) metabolite produced by intestinal microbiota in a subset of people consuming dietary soy. Equol producers may show different responses to soy foods and phenotypes related to cancer risk. Here, we assessed the effects of soy IF, endogenous microbial equol production, and dietary racemic equol in a 3 × 2 × 2 factorial experiment using gnotobiotic apoE-null mice (n = 9-11/group/sex). At age 3-6 wk, equol-producing microbiota were introduced to one-half of the colony (n = 122). At age 6 wk, mice were randomized to receive a diet that contained 1 of 3 protein sources: casein and lactalbumin, alcohol-washed soy protein (low IF), and intact soy protein (high IF), with total IF amounts of 0, 42, and 566 mg/kg diet, respectively. One-half of each diet group also received racemic equol (291 mg/kg diet). After 16 wk of dietary treatment, serum isoflavonoid profiles varied with sex, soy IF amount, and intestinal microbiota status. There were no treatment effects on tissues of male mice. In females, reproductive tissue phenotypes differed by equol-producing ability (i.e., microbiota status) but not dietary equol or IF content. Equol producers had lower uterine weight, vaginal epithelial thickness, total uterine area, endometrial area, and endometrial luminal epithelial height compared with nonproducers (P < 0.05 for all), with an association between microbiota status and estrous cycle (P > chi-square = 0.03). Exogenous equol reduced expression of progesterone receptor (PGR) and the proliferation marker Ki67 (P < 0.0001) in vaginal epithelium and endometrium; for endogenous equol, only PGR was reduced (P < 0.0005). Our findings indicate that equol diminishes estrogen-dependent tissue responses in apoE-null mice.
    Journal of Nutrition 08/2012; 142(10):1829-35. · 4.20 Impact Factor
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    ABSTRACT: Here, we report the effects of estrogen and the selective estrogen receptor modulator (SERM) levormeloxifene on adrenocortical measures in ovariectomized female cynomolgus monkeys (Macaca fascicularis). Animals were randomized into one of five treatment groups, each containing 23 to 26 animals: (1) placebo, (2) 0.016 mg/kg 17β-estradiol (E(2)), (3) 0.5 mg/kg levormeloxifene (L(1)), (4) 1.0 mg/kg levormeloxifene (L(2)), and (5) 5.0 mg/kg levormeloxifene (L(3)). Treatments were administered orally each day for 18 mo. All doses of levormeloxifene resulted in adrenal weights at least 50% greater than placebo (p < .0001 for all). The target dose of levormeloxifene (L(2)) resulted in higher serum concentrations of cortisol (+63%), dehydroepiandrosterone-sulfate (+73%), and androstenedione (+37%) compared with the placebo group (p < .05 for all). In contrast, E(2) resulted in no significant differences in adrenal weight or adrenocortical steroids. Oral E(2) and all SERM doses resulted in similar reductions in serum gonadotropins and at least threefold greater uterine weight versus placebo (p < .0001 for all). Results indicate that the SERM levormeloxifene, in contrast to E(2), may have robust stimulatory effects on adrenocortical hormones in a postmenopausal model. These findings warrant further investigation into long-term SERM effects on adrenocortical function.
    Toxicologic Pathology 01/2012; 40(1):55-61. · 2.06 Impact Factor
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    ABSTRACT: Glyceollins are stress-induced compounds in soybeans with bioactive properties distinct from parent soy isoflavones. The goals of this study were to evaluate the effects of dietary glyceollin-enriched and standard soy protein isolates and identify candidate target pathways of glyceollins on transcriptional profiles within mammary gland tissue. Thirty female postmenopausal cynomolgus monkeys were randomized to diets containing one of three protein sources for 3 weeks: (1) control casein/lactalbumin (C/L), (2) standard soy protein containing 194 mg/day isoflavones (SOY), and (3) glyceollin-enriched soy protein containing 189 mg/day isoflavones + 134 mg/day glyceollins (GLY). All diets contained a physiologic dose of estradiol (E2) (1 mg/day). All doses are expressed in human equivalents scaled by caloric intake. Relative to the control C/L diet, the GLY diet resulted in greater numbers of differentially regulated genes, which showed minimal overlap with those of SOY. Effects of GLY related primarily to pathways involved in lipid and carbohydrate metabolism, including peroxisome proliferator-activated receptor (PPAR)-γ and AMP-activated protein kinase (AMPK) signaling, adipocytokine expression, triglyceride synthesis, and lipase activity. Notable genes upregulated by the GLY diet included PPAR-γ, adiponectin, leptin, lipin 1, and lipoprotein lipase. The GLY diet also resulted in lower serum total cholesterol, specifically nonhigh-density lipoprotein cholesterol, and increased serum triglycerides as compared to the C/L diet. No effects of GLY or SOY were seen on serum insulin, adipocytokines, or vascular and bone turnover markers. These preliminary findings suggest that glyceollin-enriched soy protein has divergent effects from standard soy with some specificity for adipocyte activity and nutrient metabolism.
    Journal of Agricultural and Food Chemistry 11/2011; 60(1):81-6. · 3.11 Impact Factor
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    ABSTRACT: Breast cancer (BC) is the most common malignancy of women in the developed world. To better understand its pathogenesis, knowledge of normal breast development is crucial, as BC is the result of disregulation of physiologic processes. The aim of this study was to investigate the impact of reproductive life stages on the transcriptional profile of the mammary gland in a primate model. Comparative transcriptomic analyses were carried out using breast tissues from 28 female cynomolgus macaques (Macaca fascicularis) at the following life stages: prepubertal (n = 5), adolescent (n = 4), adult luteal (n = 5), pregnant (n = 6), lactating (n = 3), and postmenopausal (n = 5). Mammary gland RNA was hybridized to Affymetrix GeneChip(®) Rhesus Macaque Genome Arrays. Differential gene expression was analyzed using ANOVA and cluster analysis. Hierarchical cluster analysis revealed distinct separation of life stage groups. More than 2,225 differentially expressed mRNAs were identified. Gene families or pathways that changed across life stages included those related to estrogen and androgen (ESR1, PGR, TFF1, GREB1, AR, 17HSDB2, 17HSDB7, STS, HSD11B1, AKR1C4), prolactin (PRLR, ELF5, STAT5, CSN1S1), insulin-like growth factor signaling (IGF1, IGFBP1, IGFBP5), extracellular matrix (POSTN, TGFB1, COL5A2, COL12A1, FOXC1, LAMC1, PDGFRA, TGFB2), and differentiation (CD24, CD29, CD44, CD61, ALDH1, BRCA1, FOXA1, POSTN, DICER1, LIG4, KLF4, NOTCH2, RIF1, BMPR1A, TGFB2). Pregnancy and lactation displayed distinct patterns of gene expression. ESR1 and IGF1 were significantly higher in the adolescent compared to the adult animals, whereas differentiation pathways were overrepresented in adult animals and pregnancy-associated life stages. Few individual genes were distinctly different in postmenopausal animals. Our data demonstrate characteristic patterns of gene expression during breast development. Several of the pathways activated during pubertal development have been implicated in cancer development and metastasis, supporting the idea that other developmental markers may have application as biomarkers for BC.
    Breast Cancer Research and Treatment 10/2011; 133(2):617-34. · 4.47 Impact Factor
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    ABSTRACT: Estrogen independence and progression to a metastatic phenotype are hallmarks of therapeutic resistance and mortality in breast cancer patients. Metastasis has been associated with chemokine signaling through the SDF-1-CXCR4 axis. Thus, the development of estrogen independence and endocrine therapy resistance in breast cancer patients may be driven by SDF-1-CXCR4 signaling. Here we report that CXCR4 overexpression is indeed correlated with worse prognosis and decreased patient survival irrespective of the status of the estrogen receptor (ER). Constitutive activation of CXCR4 in poorly metastatic MCF-7 cells led to enhanced tumor growth and metastases that could be reversed by CXCR4 inhibition. CXCR4 overexpression in MCF-7 cells promoted estrogen independence in vivo, whereas exogenous SDF-1 treatment negated the inhibitory effects of treatment with the anti-estrogen ICI 182,780 on CXCR4-mediated tumor growth. The effects of CXCR4 overexpression were correlated with SDF-1-mediated activation of downstream signaling via ERK1/2 and p38 MAPK (mitogen activated protein kinase) and with an enhancement of ER-mediated gene expression. Together, these results show that enhanced CXCR4 signaling is sufficient to drive ER-positive breast cancers to a metastatic and endocrine therapy-resistant phenotype via increased MAPK signaling. Our findings highlight CXCR4 signaling as a rational therapeutic target for the treatment of ER-positive, estrogen-independent breast carcinomas needing improved clinical management.
    Cancer Research 01/2011; 71(2):603-13. · 9.28 Impact Factor
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    ABSTRACT: Combination estrogen + progestin therapy has been associated with increased breast cancer risk in postmenopausal women. Selective estrogen receptor modulators (SERM) are potential alternatives to progestins, although the endometrial safety of estrogen + SERM co-therapies is not known. The goal of this study was to evaluate the endometrial profile of low-dose estradiol and the SERM tamoxifen alone and in combination. Twenty-four postmenopausal female cynomolgus macaques were randomized by social group to receive placebo, low-dose micronized estradiol (E(2); 0.25 mg/1,800 kcal), the SERM tamoxifen (Tam; 20 mg/1,800 kcal), or E(2) + Tam for 4 months in a parallel-arm design. Tamoxifen alone resulted in overlapping but distinct effects compared with E(2). Both E(2) and Tam increased uterine weight and endometrial thickness, whereas only E(2) increased endometrial proliferation. Morphologic effects were similar for Tam and E(2) + Tam, which both induced stromal fibrosis and cystic change. Tamoxifen inhibited E(2)-induced proliferation and expression of genes related to cell cycle progression while exhibiting mixed agonist and antagonist effects on gene markers of estrogen receptor activity. The gene expression profile for E(2) + Tam was distinct from either E(2) or Tam alone but dominated by the Tam effect for estrogen-regulated genes. Tam also attenuated E(2) effects on both vaginal maturation and cervical epithelial height. These findings characterize a novel phenotype resulting from estrogen + SERM co-therapy. The predominance of Tam effects on endometrial proliferation, morphology, and transcriptional profiles suggests that endometrial risks for E(2) + Tam may be similar to Tam alone.
    Clinical Cancer Research 02/2010; 16(3):946-56. · 7.84 Impact Factor
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    ABSTRACT: Alpha human papillomaviruses (HPVs) are among the most common sexually transmitted agents of which a subset causes cervical neoplasia and cancer in humans. Alpha-PVs have also been identified in non-human primates although few studies have systematically characterized such types. We cloned and characterized 10 distinct types of PVs from exfoliated cervicovaginal cells from different populations of female cynomolgus macaques (Macaca fascicularis) originating from China and Indonesia. These include 5 novel genotypes and 5 previously identified genotypes found in rhesus (Macaca mulatta) (RhPV-1, RhPV-a, RhPV-b and RhPV-d) and cynomolgus macaques (MfPV-a). Type-specific primers were designed to amplify the complete PV genomes using an overlapping PCR method. Four MfPVs were associated with cervical intraepithelial neoplasia (CIN). The most prevalent virus type was MfPV-3 (formerly RhPV-d), which was identified in 60% of animals with CIN. In addition, the complete genomes of variants of MfPV-3 and RhPV-1 were characterized. These variants are 97.1% and 97.7% similar across the L1 nucleotide sequences with the prototype genomes, respectively. Sequence comparisons and phylogenetic analyses indicate that these novel MfPVs cluster together within the alpha12 PV species closely related to the alpha9 (e.g., HPV16) and alpha11 species (e.g., HPV34), and all share a most recent common ancestor. Our data expand the molecular diversity of non-human primate PVs and suggest a recent expansion of alpha-PV species groups. Moreover, identification of an overlapping set of MfPVs in rhesus and cynomolgus macaques indicates that non-human primate alpha-PVs might not be strictly species-specific and may represent past interspecies infection.
    Virology 09/2009; 393(2):304-10. · 3.35 Impact Factor
  • J Mark Cline, Charles E Wood
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    ABSTRACT: Soy isoflavones are phytoestrogenic components of dietary soy, which are widely consumed for their potential health benefits. Soy isoflavones appear to decrease breast and endometrial cancer risk in human observational studies, but paradoxically stimulate growth of breast cancer cells in culture and uterine enlargement in rodents. We have shown that these compounds are not estrogenic in cynomolgus monkeys even at relatively high doses, but that they reduce estrogen-induced proliferative responses of the breast and endometrium. This effect may be mediated through estrogen receptor interactions and/or modulation of endogenous estrogen metabolism. Interindividual variation in isoflavone absorption and metabolism contributes to the degree of estrogen antagonistic effect. Our recent studies have also shown that individual isoflavone metabolites such as glyceollins may have unique selective estrogen receptor modulator-like activity, acting as tissue-specific antagonists without agonist activity. Rodent studies and human epidemiologic data suggest that timing of exposure and dose relative to endogenous estrogen concentrations are important determinants of effect, and studies of dietary soy on breast development and pubertal maturation are under way. Because soy isoflavones are both abundant in standard monkey chow diets and widely available as dietary supplements for human beings, these findings have broad relevance to the health of human and nonhuman primates.
    American Journal of Primatology 04/2009; 71(9):722-31. · 2.46 Impact Factor
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    Charles E Wood, Cynthia J Lees, J Mark Cline
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    ABSTRACT: The goal of this pilot study was to evaluate the effects of testosterone (T) cotherapy on mammary gland and endometrial measures in a postmenopausal primate model. Twenty-five surgically postmenopausal cynomolgus monkeys were randomized by social group to receive daily treatment with (1) placebo, (2) oral micronized 17beta-estradiol (1 mg/d equivalent in women) + progesterone (200 mg/d equivalent in women) (E + P), or (3) E + P with T administered via subcutaneous pellets for 8 weeks at a high dose (15 mg) followed by 8 weeks at a low dose (1.5 mg) (E + P + T). The main outcome measures were breast and endometrial epithelial proliferation, as measured by Ki67/MIB1 immunolabeling. Intralobular breast proliferation did not differ significantly among groups after 8 weeks of treatment but was marginally higher (P = 0.03) in the E + P + T group after 16 weeks of treatment. No significant increase in proliferation was seen for E + P alone. Comparable changes in mammary gland markers of estrogen-receptor activity were seen for the E + P and E + P + T groups. In the endometrium, the addition of T did not increase endometrial glandular proliferation or estrogen-receptor activity or result in any distinct histologic changes. The findings of this study do not support the idea that T antagonizes the effects of combined hormone therapy on breast proliferation or markers of estrogen-receptor activity. Overall, the short-term effects of T cotherapy on the mammary gland and endometrium were minimal.
    Menopause (New York, N.Y.) 04/2009; 16(3):466-76. · 3.08 Impact Factor
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    J Mark Cline, Charles E Wood
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    ABSTRACT: This review describes the normal biology and physiology of the mammary gland in macaques, including the typical histologic appearance across the life span (development, reproductive maturity, lactation, and senescence). The molecular events regulating breast morphogenesis are described, as well as systemic and local hormonal regulators of mammary gland proliferation, differentiation, and function. Similarities and differences to the human breast are described. Regulatory events are illuminated by discussion of genetically modified mouse models. Tissue response markers, including immunohistochemical markers of proliferation and other hormonally induced changes and studies to date, regarding the effects of exogenous hormones, are briefly summarized. In general, estrogens stimulate progesterone receptor expression and proliferation in the mammary gland, and combinations of estrogens and progestogens cause greater proliferation than estrogens alone. Evaluation of novel chemical agents in macaques requires careful evaluation of age and hormonal context to avoid the confounding effects of mammary gland development, past reproductive history, and other influences on mammary gland morphology. The expression of proliferation markers and progesterone receptors may be used as biomarkers to measure chemically induced hormonal effects.
    Toxicologic Pathology 12/2008; 36(7):134s-141s. · 2.06 Impact Factor
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    ABSTRACT: The authors describe a selection of normal findings and common naturally occurring lesions in the reproductive system of female macaques, including changes in the ovaries, uterus, cervix, vagina, and mammary glands. Normal features of immature ovaries, uteri, and mammary glands are described. Common non-neoplastic lesions in the ovaries include cortical mineralization, polyovular follicles, cysts, ovarian surface epithelial hyperplasia, and ectopic ovarian tissue. Ovarian neoplasms include granulosa cell tumors, teratomas, and ovarian surface epithelial tumors. Common non-neoplastic uterine findings include loss of features of normal cyclicity, abnormal bleeding, adenomyosis, endometriosis, epithelial plaques, and pregnancy-associated vascular remodeling. Hyperplastic and neoplastic lesions of the uterus include endometrial polyps, leiomyomas, and rarely endometrial hyperplasia and endometrial adenocarcinoma. Vaginitis is common. Cervical lesions include endocervical squamous metaplasia, polyps, and papillomavirus-associated lesions. Lesions in the mammary gland are most often proliferative and range from ductal hyperplasia to invasive carcinoma. Challenges to interpretation include the normal or pathologic absence of menstrual cyclicity and the potential misinterpretation of sporadic lesions, such as epithelial plaques or papillomavirus-associated lesions. Interpretation of normal and pathologic findings is best accomplished with knowledge of the life stage, reproductive history, and hormonal status of the animal.
    Toxicologic Pathology 12/2008; 36(7):142s-163s. · 2.06 Impact Factor
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    ABSTRACT: Estrogen metabolism may play an important role in mammary carcinogenesis in postmenopausal women. We evaluated the effects of prior oral contraceptive (OC) treatment and current soy isoflavone consumption on endogenous estrogen metabolite concentration and biomarkers of tissue estrogen exposure in a monkey model. One hundred eighty-one female cynomolgus macaques were randomized to receive OC or placebo for 26 months premenopausally, then ovariectomized and randomized to one of three diets for 36 months: an isoflavone-depleted soy protein isolate (Soy-) diet, a diet containing soy protein isolate with a human equivalent of 129 mg isoflavone/d (Soy+), or a Soy- diet supplemented with conjugated equine estrogens (CEE+) at a human equivalent dose of 0.625 mg/d. Reverse-phase high-performance liquid chromatography directly coupled with tandem mass spectrometry was used to measure the concentrations of estrogen species in urine samples. Generally, prior OC treatment was associated with significantly reduced urinary estrogen metabolites (25-55% reduction; P<0.05 for each versus OC-). Animals that consumed isoflavones postmenopausally had increased urinary 2-hydroxyestrone and 16alpha-hydroxyestrone (50% and 56% increases, respectively), but reduced levels of 2-hydroxyestradiol, 2-methoxyestradiol, and 17-epiestriol (92%, 63%, and 66%, respectively), compared with animals fed a Soy- diet. Isoflavones did not have widespread effects on uterine or mammary proliferation biomarkers, whereas prior OC significantly reduced two of three proliferation end points in the endometrium. Premenopausal OCs may have long-term systemic effects on response to estrogen and its metabolism whereas postmenopausal dietary isoflavones may alter endogenous estrogen metabolism in a modest but selective manner.
    Cancer Epidemiology Biomarkers &amp Prevention 10/2008; 17(10):2594-602. · 4.56 Impact Factor
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    ABSTRACT: Proliferative lesions of the mammary gland are risk markers and potential precursors for the development of breast cancer in postmenopausal women. In this study we evaluated mammary epithelial proliferation and proliferative lesions in a group of 63 aged postmenopausal macaques randomized by social group to receive one of three experimental diets for 8 months: (1) control; (2) control with 17beta-estradiol (E2) at the human equivalent dose of 1.0 mg per day; and (3) control with the soy phytoestrogen equol (EQ) at the human equivalent dose of 105 mg per day. In normal mammary epithelium, treatment with E2 but not EQ resulted in greater proliferation, epithelial area, and progesterone receptor expression (P<0.05 for all). Mammary lesions included columnar cell change (26/63), columnar cell hyperplasia with and without atypia (13/63), atypical ductal hyperplasia (6/63), and atypical lobular hyperplasia (3/63). Lesions were most common within terminal ductal lobular units. The prevalence of columnar cell hyperplasia (total and atypical cases) was higher in animals treated with E2 compared to control (P<0.05 for both). Compared to normal mammary epithelium, columnar cell lesions (CCLs) showed greater constitutive expression of estrogen receptor-alpha across all groups (P<0.001) and greater expression of progesterone receptor in response to E2 (P<0.01). Independent of treatment, animals with CCLs on histology had greater gene expression of estrogen receptor-alpha and markers of estrogen receptor activity (trefoil factor 1) and proliferation (gene for Ki67 antigen) at a site contralateral to the CCL (P<0.05 for all). These findings demonstrate that the terminal ductal lobular units of the postmenopausal mammary gland contain morphologically distinct cell populations that may hyperrespond to E2 exposure, resulting in specific types of hyperplastic lesions.
    Laboratory Investigation 08/2008; 88(9):938-48. · 3.96 Impact Factor
  • Charles E Wood, Thomas C Register, J Mark Cline
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    ABSTRACT: Estrogen plus progestin hormone therapy has been associated with increased breast proliferation, breast density, and breast cancer risk in postmenopausal women, beyond that seen with estrogen alone. The goal of this study was to evaluate progestogen effects on gene expression profiles in the breast contributing to this promotional effect. Twenty-five ovariectomized adult female cynomolgus monkeys were given the following treatments (expressed as equivalent doses for women) in a randomized crossover design: (1) placebo; (2) oral estradiol (E2, 1 mg/day); (3) E2 + micronized progesterone (P4, 200 mg/day); and (4) E2 + medroxyprogesterone acetate (MPA, 2.5 mg/day). Treatments were given for two months, and breast biopsies were taken after each treatment period. On microarray analysis E2 + MPA treatment resulted in a greater number of significantly regulated genes compared to E2 + P4 and E2 alone (P < 0.0001). Treatment with E2 alone induced modest effects on select genes related to epidermal growth factor receptor (EGFR) activity which were augmented by the addition of MPA but not P4, consistent with patterns of epithelial cell proliferation. Genes induced by E2 + MPA included the EGFR ligands EGF, TGFA, and AREG, and downstream targets such as STAT5A, STAT5B, SRC, EIF4EBP1, and MYC. Progestogens showed mixed antagonistic effects on E2-induced genes which tended to be greater for P4 than MPA. These findings suggest that a standard dose of oral E2 + MPA has a more pronounced effect on gene expression in the breast compared to E2 alone or E2 + P4 and that promotional effects of E2 + MPA may be mediated in part by increased EGFR activity.
    Breast Cancer Research and Treatment 04/2008; 114(2):233-42. · 4.47 Impact Factor

Publication Stats

568 Citations
160.37 Total Impact Points

Institutions

  • 2004–2013
    • Wake Forest School of Medicine
      • • Section on Comparative Medicine
      • • Department of Pathology
      Wake Forest, NC, United States
  • 2009–2012
    • Albert Einstein College of Medicine
      • Department of Microbiology & Immunology
      New York City, New York, United States
  • 2011
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Medicine
      New Orleans, LA, United States
    • Inselspital, Universitätsspital Bern
      Berna, Bern, Switzerland
  • 2008
    • Wake Forest University
      • School of Medicine
      Winston-Salem, North Carolina, United States
  • 2007
    • Tulane University
      • Section of Hematology and Medical Oncology
      New Orleans, LA, United States