Crosstalk between the androgen receptor and progesterone receptor isoforms in breast and prostate cancer

Cabral, Angelique Aida (2018-03)

Thesis (MSc)--Stellenbosch University, 2018.

Thesis

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.

AFRIKAANSE OPSOMMING: Die groei en oorlewing van bors- en prostaatkanker is afhanklik van seine deur onderskeidelik die estrogeenreseptor (ER) en androgeenreseptor (AR). Ander steroïedreseptore soos die progesteroonreseptor (PR) is egter ook betrokke in beide kankers, en onlangse bewyse stel voor dat aansienlike wisselwerking tussen hierdie reseptore in borskanker voorkom. Ondersoeke na soortgelyke wisselwerkingsmeganismes in prostaatkanker ontbreek. Aangesien die AR en PR waarskynlik saam uitgedruk word in ‘n onderafdeling van bors- en prostaatkankers, is dit verbasend dat geen studies die wisselwerking tussen die AR en PR in hierdie kankers ondersoek het nie. Beide hierdie reseptore kan transkripsie aktiveer deur te bind aan DNS op ‘n klassieke responselement, benoem òf die progesteroonresponselement (PRE) wanneer die PR bind, òf die klassieke androgeenresponselement (ARE) wanneer die AR bind. Die AR kan egter ook bind aan ‘n AR selektiewe ARE asook die ER bindingsarea, benoem die estrogeenresponselement (ERE). Dit is onbekend of die PR isoforme, PRA en PRB, die AR selektiewe ARE en ERE soorgelyk kan aktiveer. In hierdie studie, het ons ondersoek of the PR isoforme, in die afwesigheid en teenwoordigheid van bekende PR agoniste (sintetiese promegestoon (R5020), natuurlike progesteroon (P4), en die sintetiese progestien medroksieprogesteroonasetaat (MPA)), die transaktiveringsfunksie van die AR deur die bogenoemde responselemente kon wysig in die MDA-MB-231 borskanker- en PC3 prostaatkankersellyne. Die selle was tydelik getransfekteer met die uitdrukkingsvektor vir die AR en/of PR isoforme, saam met die toepaslike promotor-rapporteerder konstrukte. Die algemene tendens wat waargeneem is, was dat beide die ligandlose en ligand-gebonde PR isoforme die aktiwiteit van die AR verhoog het in ‘n sellyn-, ligand- en/of promotor-spesifieke manier. Ons het spesifiek getoon dat PRB, beide in die afwesigheid en teenwoordigheid van PR ligande, in die algemeen AR transaktivering op verskeie responselemente in die bors- en prostaatkankerselle opreguleer. Alhoewel die AR transaktiveringsfunksie ook deur PRA verhoog was op die selektiewe ARE en ERE, het PRA die AR-bemiddelde transaktivering op die klassieke ARE verlaag. Ons het ook nuwe bewyse voorsien dat beide PR isoforme die aktiwiteit van die AR naboots op die seletiewe ARE en ERE in beide sellyne, wat ‘n meganisme mag voorsien waardeur die PR onkogeniese effekte in beide kankers kan uitvoer. Onder hierdie gebruikte eksperimentele kondisies, het ons geen selproliferasie in die teenwoordigheid van 5α-dihidrotestosteroon (DHT) in enige sellyn getransfekteer met die AR waargeneem nie. In opsomming, alhoewel die resultate van hierdie studie voorlopig is, is ons die eerste om te toon dat die transaktiveringfunksie van die AR oor die algemeen verhoog is in die teenwoordigheid van die PR isoforme in beide bors- en prostaatkanker. Hierdie bevindinge ondersteun die potensiële wisselwerkingsmeganisme tussen die AR en PR isoforme in hierdie kankers. Alhoewel die presiese fisiologiese implikasies van hierdie resultate verdere ondersoek verlang, dra ons bevindinge by tot die begrip van wisselwerking tussen steroïdreseptore, veral die AR en die PR isoforme, en hoe dit bors- en prostaankankergroei mag beïnvloed.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/103887
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