The role of androgens and polymorphisms in the androgen receptor in the epidemiology of breast cancer

Abstract

164 AR = androgen receptor; BMI = body mass index; CAG = cytosine adenine guanine; GGC = guanine guanine cytosine. Breast Cancer Research Vol 5 No 3 Lillie et al. IntroductionThe role of androgens in breast cancer etiology has been a subject of both curiosity and confusion. It is still unclear by which mechanisms testosterone exerts its activity in the female breast, and whether the effects are predominantly proliferative or anti-proliferative on breast cells at physiologic levels. In the present review we evaluate the results from epidemiologic studies on the role of circulating testosterone and a functional polymorphism in the androgen receptor (AR) in breast cancer. We also highlight some of the epidemiologic challenges in addressing these questions. Sources of endogenous testosteroneThere are two main sources of androgens in women. Testosterone is produced directly by the ovary and by conversion of the adrenal androgens dehydroepiandrosterone and dehydroepiandrosterone-sulfate into androstenedione, and then further to testosterone in peripheral tissue [1]. In premenopausal women, approximately 25% of circulating testosterone is secreted directly from the adrenal gland and 25% from the ovary, whereas the remaining 50% is produced by peripheral conversion of androstenedione [2]. Testosterone levels vary over the menstrual cycle with peak levels mid-cycle, and diurnally with highest levels in the early morning [3].Testosterone and androstenedione are produced by the interstitial cells of the ovarian stroma and may continue to respond to gonadotopins and produce testosterone after the menopause [4]. In normal postmenopausal women the ovarian vein has been observed to have higher concentrations of testosterone than is found in peripheral blood; bilateral oophorectomy results in reductions in testosterone levels by as much as 50% [5].Several smaller cross-sectional studies have found lower testosterone levels in postmenopausal than premenopausal women [6][7][8] or lower levels in perimenopausal than premenopausal women [2]. Large longitudinal studies that have followed women through the menopausal transition have observed either no significant change in testosterone [2,9] or a 15% decrease in both testosterone and androstenedione at menopause [10]. In one study of women aged 50-89 years testosterone levels were lowest at the time of the menopause, whereas women older than 70 years or more than 20 years postmenopause had levels approximating those of premenopausal women [11]. ReviewThe role of androgens and polymorphisms in the androgen receptor in the epidemiology of breast cancer AbstractTestosterone binds to the androgen receptor in target tissue to mediate its effects. Variations in testosterone levels and androgen receptor activity may play a role in the etiology of breast cancer. Here, we review the epidemiologic evidence linking endogenous testosterone to breast cancer risk. Paradoxically, results from observational studies that have examined polymorphisms in the androgen receptor suggest that the low-activ...

Serum concentrations of estrogens, sex hormone‐binding globulin, and androgens and risk of breast cancer in postmenopausal women

“…Clearly, the cumulative epidemiologic data to date leave the effect of androgens on breast cancer risk unresolved. 3 Moreover, data from cell culture and in vitro studies are inconclu- [4][5][6] The only previous study of androstenediol in relationship to breast cancer risk of which we are aware reported a positive association, consistent with our results, but the association was not adjusted for estrogens. 7 Our finding of a slight reduction in risk with increasing levels of SHBG, although not statistically significant, is similar to that from the reanalysis of the 9 prospective studies, 2 an expanded version of 2 of these studies 24,25 and other recent cohort studies.…”

“…1 The relationship between endogenous androgen levels (testosterone, androstenedione, dehydroepiandrosterone (DHEA)) and breast cancer risk is less clear, with both epidemiologic and experimental data providing conflicting results. [2][3][4][5][6] A metabolite of DHEA, 5-androstene-3b, 17b-diol (androstenediol), which in vitro acts as an estrogen in estradiol-deficient medium and as an androgen in an estrogen-rich medium, has been linked to increased breast cancer risk in postmenopausal women in one study. 7 Androgens could act to stimulate the breast directly or indirectly by providing the raw material for the synthesis of estrogens in peripheral or mammary adipose tissue.…”

Androgen Receptor and Prostate-Specific Antigen Gene Polymorphisms and Breast Cancer in African-American Women

“…The tumor growth -inhibitory effects of testosterone and dihydrotestosterone have been observed in breast cancer cell lines and in animal models (1), whereas higher circulating androgen levels have been noted in breast cancer patients compared with controls (2,3). Androgen and estrogen levels are highly correlated.…”

Implication of oestrogen in the development of breast cancer: a brief narrative review

“…Other hormones, such as progesterone, prolactin and testosterone may also be important. 6,11,12 This work explores the evidence in literature that exposure to animal oestrogen is a major determinant of risk breast cancer. It is not intended to be a comprehensive review, but focuses narratively on epidemiological and experimental data relating to the implication of oestrogen in the aetiology of breast cancer and possible mechanisms that might account for the association.…”