CONICET | Buscador de Institutos y Recursos Humanos

AACR 2007Reversibility of hormone resistance and effect of combined antiprogestins and estrogen or tamoxifen treatment in murine mammary carcinomas. Victoria Wargon, Julieta Bolado, Claudia Lanari. We have developed an experimental model in which the continuousadministration of medroxyprogesterone acetate (MPA) induces mammarycarcinomas in BALB/c mice. These ductal mammary carcinomas express high levels of estrogen (ER) and progesterone receptors (PR) and transit through different stages of hormone dependence. These tumors are inhibited by antiprogestins, estrogens and tamoxifen. We have previously reported that estrogen resistance could be reverted after several syngeneic passages in untreated mice. Recently, using the C4-HI tumor we have developed, by selective pressure, a tumor with acquired resistance to RU 486 (C4-HIR). This resistant variant was more metastatic than the parental tumor. The aim of this study was: a) to evaluate the levels of PR and ER in both sensitive and resistant variants; b) to evaluate if the acquired resistance and aggressiveness could be reverted; c) to study the effect of combined therapies in both variants. C4-HIR tumors were successively transplanted in 4 animals, 2 of which were treated with RU 486. Tumors from untreated animals were used for passages. During the 2 first passages tumors grew even in the presence of antiprogestins. After the 3rd passage (5 months later) tumors started to grow slowly in the presence of antiprogestins, and after 7 generations the tumors acquired the same sensitivity as the parental tumor. The acquisition of hormone resistance was accompanied by a significant decrease in expression of PR, mainly isoform A (PR A) and ER ¦Á as evaluated by western blots and immunofluorescence (p