Progestin drives breast cancer growth by inducing p21^CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2

Cell cycle regulator p21^CIP1 has controversial biological effects in breast cancer since in spite of its role as cell cycle inhibitor and promoter of cellular senescence, it also induces cell proliferation and chemoteraphy resistance. We here explored the molecular mechanisms involved in progestin regulation of p21^CIP1 expression. We also investigated the biological effects of p21^CIP1 in breast cancer cells. We found that the synthetic progestin medroxyprogesterone acetate (MPA) upregulates p21 ^CIP1 protein expression via c-Src, signal transducer and activator of transcription 3 (Stat3) and ErbB-2 phosphorylation. Notably, we also found that ErbB-2 nuclear function plays a key role in MPA-induction of p21^CIP1 expression. Interestingly, we determined that progestin drives p21 ^CIP1 transcriptional activation via a novel nonclassical transcriptional mechanism in which progesterone receptor is recruited along with Stat3 and ErbB-2 to a Stat3 binding site at p21^CIP1 promoter. Our findings revealed that ErbB-2 functions as a coactivator of Stat3 in progestin induction of p21^CIP1 transcriptional activation. Furthermore, we demonstrated that blockage of p21^CIP1 expression strongly inhibited in vitro and in vivo progestin-induced breast cancer cell proliferation. These results further support the hypothesis that according to cell context and type of stimulus, p21^CIP1 is capable of inducing cell cycle progression. Moreover, we provided evidence that Stat3 and nuclear ErbB-2 are key players in progestin-induced p21^CIP1 regulation.