Associations between serum testosterone levels, cell proliferation and progesterone receptor content in normal and malignant breast tissue in postmenopausal women

Abstract

Progestogens and progesterone receptors (PR) may play an important role in increased breast proliferation following combined estrogen/progestogen hormone therapy, while androgens may counteract this effect. In 50 untreated healthy postmenopausal women and 48 untreated postmenopausal breast cancer patients, we measured serum levels of testosterone (T), sex hormone-binding globulin (SHBG), estrone (E(1)) and adrenal androgens; and additionally, in the breast cancer patients, cortisol and corticosteroid-binding globulin and endocrine data related to breast proliferation (assessed using the Ki-67/MIB-1 monoclonal antibody) and PR levels (determined by enzyme immunoassay) in the breast cancer tissue. In the healthy women the percentage of MIB-1(+) cells showed significant negative correlations with serum levels of total T, calculated free T (fT) and the fT/E(1) ratio; while in the breast cancer patients PR content showed significant negative correlations with fT level, the fT/E(1) ratio and the T/SHBG ratio. No other correlations were found in any of the groups. Our findings in healthy women confirm previous reports of an antiproliferative effect of androgens in breast tissue and our finding in breast cancer patients suggests that this antiproliferative effect may be mediated via downregulation of PR.

Ontogeny of Progesterone Receptor Expression in the Subplate of Fetal and Neonatal Rat Cortex

“…The decline in the number of PR-expressing subplate neurons observed in the present study, which occurs between P5 and P14, may reflect the demise of a specific population of subplate neurons, initiated by a PR-dependent mechanism. Interestingly, progesterone can prevent or promote cell death (depending on the tissue in which its receptors are expressed), by altering expression of proapoptotic and anti-apoptotic regulatory proteins like bax and bcl-2, respectively (Amezcua et al 1999(Amezcua et al , 2000Bozdogan et al 2002;Jacobsen et al 2005;Hofling et al 2008;Yang et al 2008). Given that PR appears to be expressed in the majority of subplate neurons, it seems more likely that PR promotes cell death in this transient structure.…”

Testosterone and risk of breast cancer: appraisal of existing evidence

“…Similarly, clinical and non-human primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth, whereas conventional estrogen treatment suppresses endogenous androgens (98,99). Studies assessing tissue activity in response to serum sex steroid levels, utilizing fine needle aspiration breast biopsy, and expression of Ki-67 demonstrated a correlation with estrogens; however, no associations with androgens were found (58,59). These observations do not corroborate the notion that androgens increase breast cancer risk.…”

“…D4-Adione was initially deemed to associate with increased breast cancer risk; however, after adjustment for E 1 this risk was attenuated (56). Cross-analysis of two previously completed studies measured mammary cell proliferation via fine needle aspiration (58). Assessing cellular proliferation activity utilizing fine needle aspiration breast biopsy, in response to serum sex steroid levels, demonstrated a correlation with estrogens, but no associations with androgens were found.…”