Androgens Regulate T47D Cells Motility and Invasion through Actin Cytoskeleton Remodeling.

The relationship between androgens and breast cancer is controversial. Androgens have complex effects on breast cancer progression and metastasis. Moreover, androgen receptor (AR) is expressed in approximately 70 to 90% of invasive breast carcinomas, which has prognostic relevance in basal-like cancers and in triple-negative breast cancers. Recent studies have associated the actin-binding proteins of the ezrin-radixin-moesin (ERM) family with metastasis in endocrine-sensitive cancers. We studied on T47D breast cancer cells whether androgens with different characteristics, such as testosterone (T), dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA) may regulate breast cancer cell motility and invasion through the control of actin remodeling. We demonstrate that androgens promote migration and invasion in T47D via Moesin activation. We show that T and DHEA exert their actions via the AR and estrogen receptor (ER), while the non-aromatizable androgen - DHT - only recruits AR. We further report that androgen induced significant changes in actin organization with pseudopodia along with membrane ruffles formation, and this process is mediated by Moesin. Our work identifies novel mechanisms of action of androgens on breast cancer cells. Through the modulation of Moesin, androgens alter the architecture of cytoskeleton in T47D breast cancer cell and promote cell migration and invasion. These results could help to understand the biological actions of androgens on breast cancer and, eventually, to develop new strategies for breast cancer treatment.

Estetrol Modulates Endothelial Nitric Oxide Synthesis in Human Endothelial Cells.

Estetrol (E4) is a natural human estrogen that is present at high concentrations during pregnancy. E4 has been reported to act as an endogenous estrogen receptor modulator, exerting estrogenic actions on the endometrium or the central nervous system but presenting antagonistic effects on the breast. Due to these characteristics, E4 is currently being developed for a number of clinical applications, including contraception and menopausal hormone therapy. Endothelial nitric oxide (NO) is a key player for vascular function and disease during pregnancy and throughout aging in women. Endothelial NO is an established target of estrogens that enhance its formation in human endothelial cells. We here addressed the effects of E4 on the activity and expression of the endothelial nitric oxide synthase (eNOS) in cultured human umbilical vein endothelial cells (HUVEC). E4 stimulated the activation of eNOS and NO secretion in HUVEC. E4 was significantly less effective compared to E2, and a peculiar concentration-dependent effect was found, with higher amounts of E4 being less effective than lower concentrations. When E2 was combined with E4, an interesting pattern was noted. E4 antagonized NO synthesis induced by pregnancy-like E2 concentrations. However, E4 did not impede the modest induction of NO synthesis associated with postmenopausal-like E2 levels. These results support the hypothesis that E4 may be a regulator of NO synthesis in endothelial cells and raise questions on its peculiar signaling in this context. Our results may be useful to interpret the role of E4 during human pregnancy and possibly to help develop this interesting steroid for clinical use.

Effect of dehydroepiandrosterone on central and peripheral levels of allopregnanolone and beta-endorphin.

OBJECTIVE: To evaluate the effects of dehydroepiandrosterone (DHEA) oral administration on neuroendocrine function by investigating the modulation exerted by DHEA administration on allopregnanolone and beta-endorphin (beta-EP) central and peripheral levels in ovariectomized rats. DESIGN: Prospective study. SETTING(S): Experimental research environment. ANIMAL(S): Female Wistar rats (n = 48). INTERVENTION(S): Forty rats were ovariectomized and received an oral treatment with either placebo or 0.5, 1, or 2 mg/kg/day of DHEA. After euthanization, beta-EP levels were measured in hippocampus, hypothalamus, anterior pituitary, neurointermediate pituitary, and plasma. Allopregnanolone and DHEAS levels were measured in hippocampus, hypothalamus, anterior pituitary, adrenal glands, and serum. Serum E(2) concentration was also measured. MAIN OUTCOME MEASURE(S): Dehydroepiandrosterone sulfate ester (DHEAS), E(2), beta-EP, and allopregnanolone levels. RESULT(S): Dehydroepiandrosterone administration increased DHEAS content in all organs and serum, except for anterior pituitary, where no significant changes occurred. DHEA administration in ovariectomized animals did not significantly increase E(2) circulating levels. DHEA administration induced an increase in allopregnanolone and beta-EP content in hippocampus, hypothalamus, and anterior pituitary and in serum or plasma. CONCLUSION(S): Dehydroepiandrosterone administration in ovariectomized animals increased allopregnanolone and beta-EP central and peripheral levels, which suggests that this compound may play a role as a neuroendocrine mediator, possibly substantiating the beneficial effects of postmenopausal DHEA therapy on the central nervous system.