High incidence of mammary intraepithelial neoplasia development inMen1-disrupted murine mammary glands

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Mutations of theMEN1tumour suppressor gene predispose patients to the development of multiple endocrine neoplasia type 1 (MEN1) syndrome, which is characterized by multiple endocrine tumours, including prolactinomas. The recent findings of the interaction between menin, encoded by theMEN1gene, and the oestrogen receptor, as well as the observation of rare cases of mammary carcinomas in our heterozygousMen1mutant mice, led us to investigate a putative tumour suppressor function of theMen1gene in mouse mammary cells by disrupting the gene in luminal epithelial cells. A significantly higher incidence of mammary intraepithelial neoplasia (MIN) was observed in mutantWapCre-Men1F/F mice (51.5%) than inWapCre-Men1+/+ (0%) orMen1F/F (7.1%) control mice. The majority of MIN observed in the mutant mice displayed complete menin inactivation. Because of the leakage ofWapCretransgene expression, prolactinomas were observed in 83.3% of mutant mice, leading to premature death. As there was no correlation between MIN development and elevated serum prolactin levels, and phospho-STAT5 expression was decreased in mammary lesions, the increased incidence of MIN lesions was most likely due toMen1disruption rather than to prolactinoma development. Interestingly, in MIN lesions, we found a decrease in membrane-associated E-cadherin and beta-catenin expression, the latter of which is a menin partner. Finally, reduced menin expression was found in a large proportion of two independent cohorts of patients with breast carcinomas. Taken together, the current work indicates a role ofMen1inactivation in the development of mammary pre-cancerous lesions in mice and a potential role in human mammary cancer.

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