Progestins modulates breast cancer growth through the activation of the AP-1 transcription factor

M. CELESTE DÍAZ FLAQUÉ, WENDY BÉGUELIN, VICTORIA SUNDBLAD, CINTHIA ROSEMBLIT, CECILIA J. PROIETTI, MARTÍN A. RIVAS, MERCEDES TKACH, DELFINA MAZZA ELIZALDE, EDUARDO H. CHARREAU, ROXANA SCHILLACI, PATRICIA V. ELIZALDE

Holderness, NH, USA

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

Gordon Research Conferences

Accumulating evidence has shown the involvement of the progesterone receptor (PR) inbreast cancer development. In its classical mechanism of action, PR acts as a ligandinducednuclear transcription factor. In addition to its direct transcriptional effects, PRactivates signal transduction pathways in breast cancer cells through a rapid or nongenomicmechanism, which results in cell proliferation. Interestingly, progestin induce theexpression of key regulators of cell cycle progression which do not contain a classicalprogesterone response element (PRE) in their promoters, such as cyclin D1. In the presentstudy, we have unraveled a novel mechanism through which progestin controls breastcancer through the integration of rapid PR signaling and a transcriptional mechanism(tethering), that involves progesterone-bound PR interaction with AP-1 factors (composedof jun and fos family members), at specific AP-1 binding sites (TRE) in the cyclin D1promoter. We here found that progestin induces rapid c-jun and c-fos activation via ERK1/2 in both mouse and human breast cancer cells. Our chromatin immunoprecipitation(ChIP) assays demonstrated that progestin stimulates c-jun, c-fos, and PR recruitment tothe TRE site of the cyclin D1 promoter. The simultaneous binding of all three proteins tothe cyclin D1 promoter upon progestin stimulation was shown by using sequential ChIPassays. Consistent with previous findings, progestin induced a strong cyclin D1 proteinexpression in the human and mouse breast cancer models used in this study. Finally, wefound that inhibition of c-fos and c-jun activation by the use of dominant negative forms ofthese proteins completely blocked progestin induced cyclin D1 expression and breastcancer cell growth.