INHIBITION OF MAMMARY TUMOR GROWTH BY ANTIPROGESTIN TREATMENT IS RELATED TO AN INCREASED INTERACTION OF PROGESTERONE RECEPTORS AND SMRT AT THE CCND1 AND MYC PROMOTERS

MARINA RIGGIO; SEBASTIÁN GIULIANELLI; VICTORIA WARGON; VIRGINIA NOVARO; CLAUDIA LANARI

Smithfield, RI

Conferencia; Gordon Research Conference: Hormone-Dependent Cancers Development and Progression; 2013

An increasing body of evidence indicates that progesterone receptors (PR) represent an important regulator of breast cancer growth. In the last years our group has been investigating the mechanisms by which antiprogestins induce the regression of murine mammary carcinomas, showing that only those expressing levels of PR isoform A (PRA) higher than those of B (PRB) regress with antiprogestins (onapristone, mifepristone, Proellex®, lonaprisan or aglepristone); tumors expressing mostly PRB were either stimulated or did not respond. To corroborate the murine data we stably transfected human breast cancer cells (IBH-6) to overexpress PRA or PRB; only PRA overexpressing xenografts were inhibited by antiprogestins. Similarly, only T47D-YA xenografts were inhibited by mifepristone. No inhibitory effects were observed in xenografts overexpressing PRB. The aim of this study was to investigate the mechanisms underlying this differential effect. In in vitro studies using T47D, T47D-YA, or C4-HI (murine) cells, that are all inhibited by MFP, we showed that MFP increased the association between PR to the corepressor SMRT but not to the coactivator AIB1. MFP was unable to induce SMRT and PR interactions in PRB overexpressing cells. Moreover, ChIP assays confirmed the increased association of PR and SMRT at the same sites at the CCND1 and MYC promoters.  Preliminary results showed that the inhibition of SMRT expression by siRNA abolished the inhibitory effect of MFP on T47D cells, and now MFP stimulated cell proliferation. The results reported herein suggest that SMRT plays a pivotal role mediating MFP inhibitory effects only in a high PRA context. Our data as a whole supports our hypothesis that only patients with higher levels of PRA than PRB are candidates to an antiprogestin therapy.