Browsing by Author "Ndlovu, Easter"
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- ItemCrosstalk between the androgen and estrogen receptors in breast cancer(Stellenbosch : Stellenbosch University, 2016-03) Ndlovu, Easter; Africander, Donita; Louw, Ann; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.ENGLISH ABSTRACT: Hormone replacement therapy (HRT) is used by post-menopausal women to alleviate symptoms associated with decreased endogenous estrogen levels, such as hot flashes and vaginal dryness. Although HRT is considered an effective treatment method, results from clinical trials such as those conducted by the Women’s Health Initiative (WHI) and Million Women Study (MWS) revealed that HRT usage is associated with increased risk of invasive breast cancer. The mechanism whereby the hormones used in HRT contribute to breast cancer risk is not fully understood. These hormones elicit their biological effects by binding to intracellular steroid receptors such as the estrogen (ER) and progesterone receptor (PR). For many years it was thought that the ER is the main steroid receptor implicated in breast cancer biology, however, data in the literature suggests that crosstalk between steroid receptors play an important role in the development and progression of this disease. Recent evidence suggests that the androgen receptor (AR) can function as a tumour suppressor and thus has the potential of being a prognostic marker and therapeutic target in breast cancer. Given that the AR has been shown to inhibit the transactivation function of ERα, this raised the question of whether the AR would also inhibit the transactivation function of the ERβ subtype. Moreover, considering that ERs have both transactivation and transrepression functions, studies investigating the influence of the AR on the transrepression function of both ERα and ERβ are lacking. This study therefore investigated whether the AR, in the absence or presence of known AR agonists (the natural AR ligand 5α-dihydrotestosterone (DHT)), the androgenic progestins, medroxyprogesterone acetate (MPA) and norethisterone-acetate (NET-A)), could modulate the transcriptional activity of the ERβ. The ER- and AR-negative MDA-MB-231 breast cancer cell line, transiently transfected with expression vectors for either ERα or ERβ and the appropriate promoter-reporter construct, was used as model system. The results showed that the unliganded or liganded AR has no effect on the transactivation function of ERβ on a synthetic estrogen response element (ERE)-containing promoter but downregulates the ERβ-driven mRNA expression of the endogenous PR gene. This study also shows estradiol (E2)-induced transactivation on a synthetic ARE- and an endogenous androgen response element (ARE)-containing promoter via ERα. For transactivation via ERβ, similar results were only seen on the endogenous ARE-containing promoter. Moreover, we show for the first time that both the unliganded- and ligand-bound AR inhibits the transrepression function of ERα, while interestingly only the ligand-bound AR was able to inhibit the transrepression function of ERβ. No E2-induced cell proliferation was observed in the MDA-MB-231 cell line overexpressing either ERα or ERβ under the experimental conditions used. In conclusion, the results of this study are in agreement with previous evidence suggesting that the AR inhibits the activity of ERα. The precise physiological implications of these results remain to be determined. Finally, although the results from this study are preliminary and have certain limitations, it nonetheless highlights the fact that the role of the AR in breast cancer is a complex one. Thus, our findings may aid our understanding of crosstalk between the ER and AR signalling pathways, and how it contributes to the growth and survival of breast cancer cells.