Endogenous Estrogen, Androgen, and Progesterone Concentrations and Breast Cancer Risk Among Postmenopausal Women

Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 01/2005; 96(24):1856-65. DOI: 10.1093/jnci/djh336
Source: PubMed


Levels of endogenous hormones have been associated with the risk of breast cancer among postmenopausal women. Little research, however, has investigated the association between hormone levels and tumor receptor status or invasive versus in situ tumor status. Nor has the relation between breast cancer risk and postmenopausal progesterone levels been investigated. We prospectively investigated these relations in a case-control study nested within the Nurses' Health Study.
Blood samples were prospectively collected during 1989 and 1990. Among eligible postmenopausal women, 322 cases of breast cancer (264 invasive, 41 in situ, 153 estrogen receptor [ER]-positive and progesterone receptor [PR]-positive [ER+/PR+], and 39 ER-negative and PR-negative [ER-/PR-] disease) were reported through June 30, 1998. For each case subject, two control subjects (n = 643) were matched on age and blood collection (by month and time of day). Endogenous hormone levels were measured in blood plasma. We used conditional and unconditional logistic regression analyses to assess associations and to control for established breast cancer risk factors.
We observed a statistically significant direct association between breast cancer risk and the level of both estrogens and androgens, but we did not find any (by year) statistically significant associations between this risk and the level of progesterone or sex hormone binding globulin. When we restricted the analysis to case subjects with ER+/PR+ tumors and compared the highest with the lowest fourths of plasma hormone concentration, we observed an increased risk of breast cancer associated with estradiol (relative risk [RR] = 3.3, 95% confidence interval [CI] = 2.0 to 5.4), testosterone (RR = 2.0, 95% CI = 1.2 to 3.4), androstenedione (RR = 2.5, 95% CI = 1.4 to 4.3), and dehydroepiandrosterone sulfate (RR = 2.3, 95% CI = 1.3 to 4.1). In addition, all hormones tended to be associated most strongly with in situ disease.
Circulating levels of sex steroid hormones may be most strongly associated with risk of ER+/PR+ breast tumors.

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    • "Risk factors for the disease include high plasma oestrogen levels (Missmer et al., 2004) and high levels of oestrogen receptor (ER) expression in mammary tissue (Kurebayashi et al., 2000). In fact, the administration of anti-oestrogens constitutes one of the most useful treatments for hormone-dependent breast cancer (Mustonen et al., 2014). "
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    ABSTRACT: Some organochlorine pesticides (OCs) have been individually linked to breast cancer (BC) because they exert oestrogenic effects on mammary cells. However, humans are environmentally exposed to more or less complex mixtures of these organochlorines, and the biological effects of these mixtures must be elucidated. In this work we evaluated the in vitro effects exerted on human BC cells by the OC mixtures that were most frequently detected in two groups of women who participated in a BC case-control study developed in Spain: healthy women and women diagnosed with BC. The cytotoxicity, oestrogenicity, and androgenicity of the most prevalent OC mixtures found in healthy women (H-mixture) and in BC patients (BC-mixture) were tested at concentrations that resembled those found in the serum of the evaluated women. Our results showed that both OC mixtures presented a similar oestrogenic activity and effect on cell viability, but BC-mixture showed an additional anti-androgenic effect. These results indicate that although the proliferative effect exerted by these mixtures on human breast cells seems to depend mainly on their oestrogenic action, the BC-mixture might additionally induce cell proliferation due to its anti-androgenic activity, therefore increasing the carcinogenic potential of this mixture. The findings of this study demonstrate that subtle variations in the composition of a mixture may induce relevant changes in its biological action. Copyright © 2015. Published by Elsevier B.V.
    Science of The Total Environment 08/2015; 537:197-202. DOI:10.1016/j.scitotenv.2015.08.016 · 4.10 Impact Factor
    • "After menopause, the concentration of progesterone in the blood decreases as the ovaries cease to function. However, progesterone can still be formed in the adrenal gland and in some other peripheral tissues, including cancerous endometrium [9] [10] [11]. Progesterone that is formed locally de novo from cholesterol can act in the same cell (intracrine action) or on neighboring cells (paracrine action) via progesterone receptors [9], or it can be further metabolized. "
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    ABSTRACT: Endometrial cancer is the most frequently diagnosed gynecological malignancy. It is associated with prolonged exposure to estrogens that is unopposed by progesterone, whereby enhanced metabolism of progesterone may decrease its protective effects, as it can deprive progesterone receptors of their active ligand. Furthermore, the 5α-pregnane metabolites formed can stimulate proliferation and may thus contribute to carcinogenesis. The aims of our study were to: 1) identify and quantify progesterone metabolites formed in the HEC-1A and Ishikawa model cell lines of endometrial cancer; and 2) pinpoint the enzymes involved in progesterone metabolism, and delineate their roles. Progesterone metabolism studies combined with liquid chromatography–tandem mass spectrometry enabled identification and quantification of the metabolites formed in these cells. Further quantitative PCR analysis and small-interfering-RNA–mediated gene silencing identified individual progesterone metabolizing enzymes and their relevant roles. In Ishikawa and HEC-1A cells, progesterone was metabolized mainly to 20α-hydroxy-pregn-4-ene-3-one, 20α-hydroxy-5α-pregnane-3-one, and 5α-pregnane-3α/β,20α-diol. The major difference between these cell lines was rate of progesterone metabolism, which was faster in HEC-1A cells. In the Ishikawa and HEC-1A cells, expression of AKR1C2 was 110-fold and 6,800-fold greater, respectively, than expression of AKR1C1, which suggests that 20-ketosteroid reduction of 5α-pregnanes and 4-pregnenes is catalyzed mainly by AKR1C2. AKR1C1/AKR1C2 gene silencing showed decreased progesterone metabolism in both cell lines, thus further supporting the significant role of AKR1C2. SRD5A1 was also expressed in these cells, and its silencing confirmed that 5α-reduction is catalyzed by 5α-reductase type 1. Silencing of SRD5A1 also had the most pronounced effects, with decreased rate of progesterone metabolism, and consequently higher concentrations of unmetabolized progesterone. Our data confirm that in model cell lines of endometrial cancer, AKR1C2 and SRD5A1 have crucial roles in progesterone metabolism, and may represent novel targets for treatment.
    Chemico-Biological Interactions 11/2014; 234. DOI:10.1016/j.cbi.2014.11.012 · 2.58 Impact Factor
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    • "Collaborative Group / Steroids 99 (2015) 49–55 53 spectrometry assays; the reason for this is not known but might again be due to cross-reactivity in the direct assay methods. The relative risk analyses showed strong positive associations of all three hormones with breast cancer risk, as previously reported by this collaborative group [6] and by subsequent individual studies [9] [13] [14] [16] [18] [20] [23] [25] [30] [31]. There were no striking or statistically significant differences between the results from the different assay methods, but this should be re-evaluated as prospective data accumulate because further data from the more accurate assay methods might reveal differences. "
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    ABSTRACT: Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study.
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