GIULIANELLI Sebastian Jesus
congresos y reuniones científicas
The nuclear association among ERalpha- PR - AIB1 is modulated by progestins and antiprogestins in experimental breast cancer
Orlando, Florida
Conferencia; AACR 102nd Annual Meeting 2011; 2011
Institución organizadora:
The nuclear receptor coactivator AIB1 (SRC-3) is intimately associated with hormone action in estrogen receptor (ER)-positive breast cancer, and its overexpression has been associated with early resistance to endocrine therapy. In two models of ER+, progesterone receptor (PR)+ breast cancer, human T47D cells growing in vitro and C4-HD and C4-HI mouse mammary carcinomas maintained by syngeneic transplantations in BALB/c mice, we have shown that progestins induce a nuclear physical association between ERa and PR isoform A (PRA). We hypothesize that this interaction is necessary to induce progestin-induced cell proliferation. While both the pure antiestrogen ICI 182780 (ICI) and the antiprogestin RU486 inhibit tumor growth, only ICI blocked the ERa-PRA nuclear interaction induced by medroxyprogesterone acetate (MPA). RU486 showed an agonist-like effect stimulating the association between both receptors. The aim of this study was to investigate the interaction of ERa with PR isoform B (PRB) in both models and to evaluate the role of AIB1 in progestin-induced proliferation and in RU486-induced inhibition of cell proliferation. MPA (10nM) treatment induced an early increase in the nuclear co-localization between pSer118 ERa and pSer162 PRB in epithelial cells from the mouse model (p<0.001), and between total ERa with pSer162 PRB in T47D cells (p<0.001), as shown by confocal microscopy. By co-immunoprecipitation assays we corroborated that both PR isoforms interact with ERa in the cell nuclei. We also found that MPA increased the nuclear association of pSer294 PR and ERa with AIB1 in the murine epithelial tumor cells (p<0.001). These results were corroborated by co-immunoprecipitation in nuclear extracts from untreated or MPA-treated T47D cells. RU486 (10nM) induced similar ERa-PR interactions as MPA, but no association between PR and AIB1 was observed in RU486-treated cells. Our data support the hypothesis that a nuclear complex of ERa, both PR isoforms, and AIB1 mediates the proliferative effects of MPA. In addition, the results suggest that the lack of association of ERa-PR complexes with AIB1 may explain the antagonist effect of RU486 in these cells, supporting the hypothesis that the inhibitory effects of RU486 are related to genomic events.