Abstract 1319: Early tumor regression after endocrine and kinase inhibitor treatments in mammary carcinomas with different hormonal requirements
Authors: Polo Maria Laura , Riggio Marina , Wargon Victoria , Giulianelli Sebastian , Vanzulli Silvia I. , Lanari Claudia , Novaro Virginia 
Published: June 2012

Two-thirds of diagnosed breasts cancers express either estrogen receptors (ER), progesterone receptors (PR) or both. Unlike most experimental breast cancer models, in the medroxyprogesterone acetate (MPA) model, MPA induces mammary carcinomas that express high levels of ER and PR. In this model we developed a tumor variant that depends on MPA to grow (C4-HD), and another one that grows without it (C4-HI). Previous studies showed that both types of tumors represent a useful tool to study mechanisms of regression after endocrine therapy, since both regress, albeit differently, after prolonged treatment (10 days) with the antiprogestin mifepristone. While regressive C4-HD tumors display extensive apoptosis, C4-HI tumors regress showing increased glandular differentiation. In order to investigate specific mechanisms of regression and to determine if these mechanisms are tumor specific or antitumor agent specific, we evaluated early steps of tumor regression caused by different agents in C4-HD and C4-HI tumors. We evaluated mifepristone (12mg/kg/day), ER modulators such as ICI182780 (25mg/kg) and tamoxifen (5mg/kg/day), and the PI3K/AKT inhibitor wortmannin (1 mg/kg/day). Mice carrying C4-HD or C4-HI tumors were treated for 48 hours and then sacrificed. Tumors were measured, excised and processed for histopathological and immunohistochemical studies as well as western blotting.

We found that after 48 hs of treatment the size of C4-HD tumors was only reduced with mifepristone (p&lt;0.001). However, even a short exposure of these tumors to any of the treatments increased apoptosis and necrosis index and stromal area, with mifepristone and tamoxifen being the most effective (p&lt;0.001 and 0.01 respectively). In C4-HI tumors, we did not observe an increase in apoptosis or necrosis index neither a significant stromal reaction after 48 hs with any treatment tested. However, all treatments caused tissular reorganization and differentiation, being the most effective mifepristone and wortmannin. To study tissue reorganization we evaluated the expression of differentiation markers such as the apical marker MUC-1 and the luminal cell marker cytoqueratin 8 and found that these markers are increased in C4-HI tumors treated with wortmannin and mifepristone (p&lt;0.01).

Taken together, these results suggest that each tumor variant has its own mechanism of regression in response to endocrine or kinase inhibitor treatments. Such different mechanism of regression in each tumor type may arise as a result of specific tumor-stromal interactions. Understanding the particular cellular mechanisms that lead to each tumor type regression could provide the basis to develop more specific and selective new antitumor therapies or potentiate therapies that already exist.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1319. doi:10.1158/1538-7445.AM2011-1319