Invited Speaker, Full Lecture: Progesterone receptor rapid activation of signaling pathways modulate nonclassical transcriptional effects

PATRICIA V. ELIZALDE

Cavtat/ Dubrovnik, Croatia September 25-29, 2009.

Congreso; EMBO Nuclear Receptor Meeting, Cavtat/ Dubrovnik, Croatia September 25-29, 2009. Session VI, Development and Cancer; 2009

EMBO ORGANIZATION -Nuclear Receptor Meeting-

Progesterone receptor (PR) plays an important role in breast cancer development However, the molecular mechanisms underlying PR proliferative effects in breast tumor cells remain poorly understood.   In its classical mechanism of action, PR acts as a ligand-induced nuclear transcription factor, interacting directly with specific progesterone response elements (PREs) in the promoter of target genes. In addition to its transcriptional effects, PR activates signal transduction pathways in breast cancer cells through a rapid or nongenomic mechanism. Interestingly, progestin induces the expression of key regulators of cell cycle progression which do not contain a classical progesterone response element (PRE) in their promoters, such as cyclin D1.  In the present study, we have unraveled novel mechanisms of progestin-induced breast tumor growth through the rapid activation of signaling pathways that in turn regulate nonclassical PR transcriptional effects. Our findings demonstrated that progestin stimulates the rapid activation of ErbB-2, a receptor tyrosine kinase, its nuclear translocation, and the assembly of a new class of transcriptional complex in which ErbB-2 acts as a coactivator of signal transducer and activator of transcription 3 (Stat3) in progestin- induced cyclin D1 promoter activation. On the other hand, we here found that through the rapid activation of c-jun and c-fos, members of the AP-1 transcription factor, progestin induces progesterone-bound PR tethering to  AP-1 in its specific binding sites (TREs) at the cyclin D1 promoter, a nonclassical transcriptional mechanism. Consistent with previous findings, progestin induced a strong cyclin D1 protein expression in the human and mouse breast cancer models used in this work. One of the most exciting findings of this study was that inhibition of progestin-induced assembly of the ErbB-2/Stat3 nuclear complex or abrogation of PR tethering to the AP-1 transcription factor resulted not only in blockage of cyclin D1 protein expression but also in abolishment of both in vitro and in vivo progestin-induced breast tumor growth.