Premium
High incidence of mammary intraepithelial neoplasia development in Men1 ‐disrupted murine mammary glands
Author(s) -
Seigne Christelle,
Auret Magdalena,
Treilleux Isabelle,
Bonnavion Rémy,
Assade Fouzia,
Carreira Christine,
GoddardLéon Sophie,
Lavergne Emilie,
Chabaud Sylvie,
Garcia Amandine,
Mazoyer Sylvie,
Lu Jieli,
Bachelot Thomas,
Frappart Lucien,
Zhang Chang Xian
Publication year - 2013
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4146
Subject(s) - men1 , multiple endocrine neoplasia , cancer research , biology , medicine , endocrinology , mammary gland , tumor suppressor gene , genetically modified mouse , transgene , breast cancer , gene , cancer , carcinogenesis , genetics
Mutations of the MEN1 tumour 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 the MEN1 gene, and the oestrogen receptor, as well as the observation of rare cases of mammary carcinomas in our heterozygous Men1 mutant mice, led us to investigate a putative tumour suppressor function of the Men1 gene in mouse mammary cells by disrupting the gene in luminal epithelial cells. A significantly higher incidence of mammary intraepithelial neoplasia ( MIN ) was observed in mutant WapCre ‐Men1 F/F mice (51.5%) than in WapCre‐Men1 +/+ (0%) or Men1 F/F (7.1%) control mice. The majority of MIN observed in the mutant mice displayed complete menin inactivation. Because of the leakage of WapCre transgene 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 to Men1 disruption 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 of Men1 inactivation in the development of mammary pre‐cancerous lesions in mice and a potential role in human mammary cancer.