Browsing by Author "Cabral, Angelique Aida"
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- ItemCrosstalk between the androgen receptor and progesterone receptor isoforms in breast and prostate cancer(Stellenbosch : Stellenbosch Univesity, 2018-03) Cabral, Angelique Aida; Africander, Donita; Storbeck, Karl-Heinz; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.ENGLISH ABSTRACT: Breast and prostate cancer growth and survival are dependent on signalling via the estrogen receptor (ER) and androgen receptor (AR), respectively. However, other steroid receptors such as the progesterone receptor (PR), are also implicated in both cancers, and emerging evidence suggests considerable crosstalk between these steroid receptors in breast cancer. Investigations into similar crosstalk mechanisms are lacking in prostate cancer. As the AR and PR are likely co-expressed in a subset of breast and prostate cancers, it is surprising that no studies have investigated crosstalk between the AR and PR in these cancers. Both these receptors can activate transcription by binding to DNA on a classical response element, termed either the progesterone response element (PRE) when the PR is bound, or the classical androgen response element (ARE) when the AR is bound. However, the AR can also bind to an AR-selective ARE as well as to the ER binding site, termed the estrogen response element (ERE). Whether the PR isoforms, PRA and PRB, can similarly activate the AR-selective ARE and ERE is not known. In this study, we investigated whether the PR isoforms, in the absence and presence of known PR agonists (synthetic promegestone (R5020), natural progesterone (P4), and synthetic progestin medroxyprogesterone acetate (MPA)), could modulate the transactivation function of the AR via the above-mentioned response elements in the MDA-MB-231 breast cancer and PC3 prostate cancer cell lines. The cells were transiently transfected with the expression vectors for the AR and/or PR isoforms, together with the applicable promoter-reporter constructs. The general trend observed was that both the unliganded and liganded PR isoforms augmented AR activity in a cell line-, ligand- and/or promoter-specific manner. Specifically, we showed that PRB, both in the absence and presence of PR ligands, generally upregulated AR transactivation on the various response elements in the breast and prostate cancer cells. While AR transactivation function was also increased by PRA on the selective ARE and ERE, PRA decreased AR-mediated transactivation on the classical ARE. We also provide novel evidence that both PR isoforms mimic AR activity on the selective ARE and the ERE in both cell lines, which may provide a mechanism through which the PR mediates oncogenic effects in both cancers. We did not observe cell proliferation in the presence of 5α-dihydrotestosterone (DHT) in either cell line transfected with the AR under the experimental conditions used in this study. In summary, even though the results from this study are preliminary, we are the first to show that the transactivation function of the AR is generally enhanced in the presence of the PR isoforms in both breast and prostate cancer. These findings support a potential crosstalk mechanism between the AR and PR isoforms in these cancers. Although the precise physiological implications of these results require further investigation, our findings contribute to the understanding of crosstalk between steroid receptors, particularly the AR and the PR isoforms, and how this may influence breast and prostate cancer cell growth.