Abstract 1387: The ratio of progesterone receptor isoforms predicts progestin and antiprogestin response: Interaction of PR with AIB1 or SMRT.
Authors: Marina Riggio, Sebastián Giulianelli, Victoria Wargon, Virginia Novaro, Claudia Lanari
Journal: Cancer Research (2013)

Abstract We have previously demonstrated in a mouse model of breast cancer that mammary carcinomas which are responsive to the antiprogestin mifepristone (MFP) express higher levels of isoform A of progesterone receptor (PRA) than isoform B (PRB). PRB is predominant in tumors with constitutive or acquired resistance to MFP, indicating that the PR isoform ratio might predict antiprogestin responsiveness. The aim of this study was to evaluate the effect of MFP and of medroxyprogesterone acetate (MPA) on the growth of human breast cancer xenografts showing different ratios of PR isoforms. We chose IBH-6 cells since they express hormone receptors and they give rise to tumor xenografts without the need of exogenous hormone supply. IBH-6 tumors express higher levels of PRB than PRA and they are not inhibited by antiprogestin treatment. We stably transfected these cells with PRA, PRB or empty vector and sc inoculated 106 transfected cells into the right flank of female nude (nu/nu) mice. When tumors reached a size of 9 mm2, animals were treated sc with MFP (10 mg/kg/day), MPA (20 mg depot) or vehicle. Interestingly, only tumors showing higher levels of PRA than PRB were inhibited with MFP treatment (p&amp;lt;0.001). This inhibition was associated with a decrease in Cyclin D1 and MYC expression as determined by western blots (p&amp;lt;0.01). On the other hand, empty vector or PR-B transfected xenografts were stimulated with MFP treatment (p&amp;lt; 0.05). The effect of MPA was not as clear as that of MFP. A slight growth inhibition of PRB transfected cells was observed (p&amp;lt; 0.05). To evaluate the molecular mechanisms involved in MFP-induced inhibitory or stimulatory effects we used wt T47D cells with equimolar PRA and PRB, as well as T47D-YA and -YB cell lines that only express PRA or PRB, respectively. Using confocal studies we showed that in wt T47D and T47D-YA cells, MPA (10 nM; 30 min) treatment induced nuclear co-localization of PR and the coactivator AIB1, while MFP (10 nM; 30 min) treatment promoted PR co-localization with the corepresor SMRT. Interestingly T47D-YB cells showed the opposite pattern: while MPA treatment promoted PR and SMRT co-localization, MFP treatment induced PR and AIB1 co-localization. Ongoing experiments will determine if these coregulators interact with PR at the MYC or CCND1 promoters. The results obtained herein using a human breast cancer xenograft model support our hypothesis that predicts that only breast cancers expressing high levels of PRA are candidates for antiprogestin treatment. Citation Format: Marina Riggio, Sebastián Giulianelli, Victoria Wargon, Virginia Novaro, Claudia Lanari. The ratio of progesterone receptor isoforms predicts progestin and antiprogestin response: Interaction of PR with AIB1 or SMRT. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1387. doi:10.1158/1538-7445.AM2013-1387