Reversal of hormone resistance and effects of combined antiprogestins and estrogen/tamoxifen treatment in murine mammary carcinomas

VICTORIA WARGON, JULIETA BOLADO AND CLAUDIA LANARI

LOS ANGELES, USA

Congreso; AACR; 2007

We have developed an experimental model in which the administration of medroxyprogesterone acetate induces mammary carcinomas in BALB/c mice. These tumors express high levels of estrogen (ER) and progesterone receptors (PR) and transit through different stages of hormone dependence. They 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 is 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 tumors; b) to evaluate if the acquired resistance and aggressiveness could be reverted; c) to study the effect of combined therapies in both tumor types. C4-HIR tumors were successively transplanted sc. in 4 animals, 2 of which were treated with RU 486. Tumors from untreated animals were used for further passages. During the 2 first passages tumors grew even in the presence of antiprogestins. After the 3rd passage (5 months) tumors started to grow slowly in the presence of antiprogestins, and after 5 generations (8 months) the tumors acquired the same sensitivity as the parental tumor. The acquisition of hormone resistance was accompanied by a significant decrease in ER and PR expression, mainly isoform A (PR A), as evaluated by western blot and immunofluorescence (p<0.05). Curiously, the reverted tumors, acquired the same pattern of ER and PR expression of the original C4-HI although the metastatic phenotype was not reverted. The responsiveness of C4-HI and C4-HIR to 17-â-estradiol (E2, 5mg pellets) and/or RU 486 (12mg/kg/day) and to tamoxifen (0.1mg/kg/day) and /or RU486 (6mg/kg/day) was evaluated. When tumors had a size of 75 mm2 treatments were initiated. Animals were followed for one month. Combined treatments induced a higher decrease in tumor size as compared with single treatments. The effect of the additive treatments was more noticeable when the resistant tumor was used. E2 induced the re-expression of PR in C4-HIR restoring RU 486 sensitivity. In summary, our results corroborate our previous findings suggesting that tumors expessing high PR A and ER levels are those sensitive to antiprogestins. Our data suggest that epigenetic mechanisms may be down regulating hormone receptors rendering the tumors unsensitive to treatment. In the process of selective pressure, a genotypic selection of more aggressive clones may favor tumor progression; however, this increase in aggressiveness is unidirectional, and could be dissociated from the ability of tumors to respond to a hormone therapy. Our data also highlight the benefit of the use of antiprogestins in addition to tamoxifen or estrogens in the management of breast cancer.