Nonclassical both transcriptional and rapid progestin effects modulate breast cancer growth

DÍAZ FLAQUÉ, M.C.; BÉGUELIN, W.; SUNDBLAD, V.; ROSEMBLIT, C.; PROIETTI, C.; RIVAS, M.; TKACH, M.; MAZZA ELIZALDE D, CHARREAU, EH.; SCHILLACI, R.; ELIZALDE, PV

Holderness NH, USA

Congreso; Gordon Research Conference Hormone Action in Development & Cancer; 2009

Gordon research Conferences

Progestin modulates breast cancer growth through the activation of the AP-1 transcription factor. MC Díaz Flaqué, W Beguelin , C Rosemblit , CJ Proietti, MA Rivas, M Tkach, DC Mazza Elizalde, EH Charreau, R Schillaci, PV Elizalde. Accumulating evidence has shown the involvement of the progesterone receptor (PR) in breast cancer development. In its classical mechanism of action, PR acts as a ligand-induced nuclear transcription factor. In addition to its direct transcriptional effects, PR activates signal transduction pathways in breast cancer cells through a rapid or nongenomic mechanism, which results in cell proliferation. Interestingly, progestin induce 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 a novel mechanism through which progestin controls breast cancer through the integration of rapid PR signaling and a transcriptional mechanism (tethering), that involves progesterone-bound PR interaction with AP-1 factors (composed of jun and fos family members), at specific AP-1 binding sites (TRE) in the cyclin D1 promoter. We here found that progestin induces rapid c-jun and c-fos activation via ERK 1/2 in both mouse and human breast cancer cells. Our chromatin immunoprecipitation (ChIP) assays demonstrated that progestin  stimulates c-jun, c-fos, and PR recruitment to the TRE site of the cyclin D1 promoter. The simultaneous binding of all three proteins to the cyclin D1 promoter upon progestin stimulation was shown by using sequential ChIP assays. Consistent with previous findings, progestin induced a strong cyclin D1 protein expression in the human and mouse breast cancer models used in this study.  Finally, we found that inhibition of c-fos and c-jun activation by the use of dominant negative forms of these proteins completely blocked progestin induced cyclin D1 expression and  breast cancer cell growth.