|Resistance of C57BL/6 mice to progestin-induced mammary carcinogenesis is associated with decreased hormone responsiveness and low basal levels of estrogen receptors alpha and progesterone receptor isoform A.

GUADALUPE MONTERO GIRARD, SILVIA I. VANZULLI, JULIETA BOLADO, ALFREDO MOLINOLO* AND CLAUDIA LANARI

Washington DC

Congreso; American Association of Cancer Research; 2006

AACR

We have previously demonstrated that medroxyprogesterone acetate (MPA) induces in BALB/c female mice invasive ductal mammary carcinomas whereas progesterone (Pg) induces mammary carcinomas of the lobular type. The aim of this study was to evaluate whether C57BL/6 mice were susceptible to MPA induced mammary carcinogenesis as BALB/c mice. Two month old C57BL/6 female mice (n=38) were treated with 40mg MPA depot every three months for twelve months or with 40mg MPA pellets replaced after 6 months for 14 months (n= 40) and in both experiments no mammary tumors were registered in C57BL/6 treated or untreated mice. Whole mount (WM) studies of mammary glands 4 revealed no MPA effects as compared with BALB/c mice which showed paraductal branching and duct distortions. Short term experiments were designed to compare Pg and MPA effects on mammary glands of both strains. Two month old female mice of both strains were sc implanted with 40 mg silastic pellets of MPA, Pg or placebo (4/group). After 2 months mammary glands were either fixed for histological evaluation or used in WM studies. MPA induced an increase in ductal branching and Pg induced a higher lobular differentiation mainly in BALB/c mice. Hormone receptors were evaluated by immunohistochemistry using validated antibodies. ERa and PR A expression were higher (p<0.05) in control BALB/c mice than in C57BL/6 mice and their expression was down regulated in progestin treated mice. PR B levels were low in control mice of both strains and increased mainly in MPA-treated mice of both strains. Other parameters such as salivary gland morphology and increase in body weight were similar in MPA- treated mice of both strains. In summary in this study we have demonstrated that a) C57BL/6 female mice are resistant to MPA induced carcinogenesis, b) their mammary glands respond very poorly to progestins, c) they show lower levels of ERa and PR A than BALB/c mice d) MPA and Pg have early different effects in mammary gland morphology e) progestins down regulate PR A but upregulate PR B. Our data suggests that the C57BL/6 genetic background may not be appropriate to study mammary carcinogenesis. The association between high basal levels of ERa and PR A with increased hormone responsiveness and mammary cancer susceptibility described herein may have clinical implications.