Browsing by Author "Van der Meer, Yolandi"
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- ItemInvestigating progesterone and estrogen receptor crosstalk in breast cancer(Stellenbosch : Stellenbosch University, 2017-03) Van der Meer, Yolandi; Africander, Donita; Louw-du Toit, Renate; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.ENGLISH ABSTRACT: Progestins are synthetic compounds designed to mimic the natural hormone progesterone (Prog), and are widely used in hormone replacement therapy (HRT) and contraception. These compounds can be divided into four generations, with newer generations increasing in progesterone receptor (PR) specificity. Although progestins have many therapeutic benefits, a number of undesirable side-effects, such as increased risk of breast cancer, have been reported. As a result, many postmenopausal women have sought alternatives for HRT, such as compounded bio-identical hormones like bio-identical Prog (bProg), claimed not to increase breast cancer risk. Progestins, Prog and bProg (collectively referred to as progestogens) elicit their biological effects primarily by binding to the PR, which exists as two predominant isoforms, PR-A and PR-B, with PR-B being the more transcriptionally active and proliferative isoform in breast cancer. Emerging evidence suggest that the PR plays an important role in breast cancer development and progression, and that there is crosstalk between the PR and estrogen receptor (ER)-α, a major etiological factor in breast cancer biology. Moreover, it has been shown that ER-α is required for PR-B-mediated effects of medroxyprogesterone acetate (MPA) on activation of gene expression and breast cancer cell proliferation. The latter raised the questions of whether ER-α is needed for PR-B-mediated effects of other progestins, and whether the ERβ subtype would also be required. Given that PR-B has both transactivation and transrepression functions, this study used transactivation and transrepression transcriptional assays to investigate the PR-B-mediated agonist efficacies and potencies of Prog, bProg and select progestins from different generations (MPA, norethisterone acetate (NET-A), levonorgestrel (LNG), gestodene (GES) and drospirenone (DRSP)), and whether these were modulated by ERα and/or ERβ. Furthermore, the effects of the progestogens on breast cancer cell proliferation were evaluated in the absence and presence of ERα- and ERβ-specific antagonists. Results showed that progestins mostly displayed similar agonist efficacies and potencies for transactivation and transrepression via PR-B. The exception was first generation MPA that was less efficacious for transactivation and least potent for transrepression, and third generation GES that was more potent for transactivation. This study is the first to show that ERα and ERβ differentially decreased PR-B-mediated agonist efficacies of progestogens for transactivation and transrepression. However, the ERα-specific antagonist had no effect on progestogen-induced expression of the endogenous PR-B regulated c-myc gene or repression of the interleukin (IL)-8 gene in the T47D breast cancer cell line, while the ERβ-specific antagonist had no effect on progestogen-induced c-myc gene expression, and appeared to abolish repression of the IL-8 gene. Additionally, we showed that all progestogens, except NET-A and DRSP, displayed similar proliferative efficacies and potencies for cell proliferation. Interestingly, while the ERα-specific antagonist had no effect on progestogen-induced cell proliferation, increased cell proliferation by LNG- and GES was enhanced by the ERβ-specific antagonist. Taken together, the results from this study, although having limitations, emphasizes the complexity of crosstalk between the PR and ER subtypes in breast cancer. Although the physiological implications of these results have to be evaluated, our findings may assist us in our understanding of crosstalk between PR-B and the ER subtypes, and how it may be contributing to progestin-induced breast cancer cell growth.