Rosiglitazone Activates ERα and PPARγ Altering Their Crosstalk and Effect on Proliferation in Cancer Cells

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We have previously shown that the expression of Estrogen Receptor alpha (ERα) inhibits Peroxisome Proliferator Activated-Receptor gamma (PPARγ) transactivation in breast cancer (MDA-MB 231) cells. Here we analyzed the physiological consequence of the interaction between ERα and PPARγ and its prevalence in other cancer cells. We demonstrate that although expressing ERα in MDA-MB-231 cells has no effect alone on proliferation, it increases Rosiglitazone (Rosi) induced growth inhibition. This is supported by the finding that Rosi can induce ERE (ER Response Element) reporter activity in MCF-7 breast cancer cells. 22Rv1 cells, an androgen responsive prostate cancer cell devoid of both ERα and PPARγ, were used to delineate the role that each receptor plays in the ensuing crosstalk. In these cells, Rosi’s induction of ERE reporter activity is ERα dependent and suppressed by the expression of PPARγ. Alternately, ERα’s inhibition of a PPRE (PPAR response element) reporter is blocked by Rosi treatment. Interestingly, we found that the expression of PPARγ decreases 22Rv1 cell proliferation in untreated cells but increases proliferation in response to low concentrations of Rosi. Furthermore, although the expression of ERα has no effect alone on 22Rv1 proliferation, it prevents PPARγ from inhibiting growth in unstimulated cells, but enhances PPARγ induced growth with Rosi treatment. Thus it is evident that there is a very complex and dynamic interplay occurring between ERα and PPARγ that is both tissue and ligand specific and results in modifications in functional responses. Furthermore Rosi induces both ERα and PPARγ activation changing the crosstalk between them and subsequent effect on proliferation.