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Integrin ?v?3 drives slug activation and stemness in the pregnant and neoplastic mammary gland.

ABSTRACT: Although integrin ?v?3 is linked to cancer progression, its role in epithelial development is unclear. Here, we show that ?v?3 plays a critical role in adult mammary stem cells (MaSCs) during pregnancy. Whereas ?v?3 is a luminal progenitor marker in the virgin gland, we noted increased ?v?3 expression in MaSCs at midpregnancy. Accordingly, mice lacking ?v?3 or expressing a signaling-deficient receptor showed defective mammary gland morphogenesis during pregnancy. This was associated with decreased MaSC expansion, clonogenicity, and expression of Slug, a master regulator of MaSCs. Surprisingly, ?v?3-deficient mice displayed normal development of the virgin gland with no effect on luminal progenitors. Transforming growth factor ?2 (TGF-?2) induced ?v?3 expression, enhancing Slug nuclear accumulation and MaSC clonogenicity. In human breast cancer cells, ?v?3 was necessary and sufficient for Slug activation, tumorsphere formation, and tumor initiation. Thus, pregnancy-associated MaSCs require a TGF-?2/?v?3/Slug pathway, which may contribute to breast cancer progression and stemness.

SUBMITTER: Desgrosellier JS

PROVIDER: S-EPMC4147869 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Integrin αvβ3 drives slug activation and stemness in the pregnant and neoplastic mammary gland.

Desgrosellier Jay S JS Lesperance Jacqueline J Seguin Laetitia L Seguin Laetitia L Gozo Maricel M Kato Shumei S Franovic Aleksandra A Yebra Mayra M Shattil Sanford J SJ Cheresh David A DA

Developmental cell 20140801 3

Although integrin αvβ3 is linked to cancer progression, its role in epithelial development is unclear. Here, we show that αvβ3 plays a critical role in adult mammary stem cells (MaSCs) during pregnancy. Whereas αvβ3 is a luminal progenitor marker in the virgin gland, we noted increased αvβ3 expression in MaSCs at midpregnancy. Accordingly, mice lacking αvβ3 or expressing a signaling-deficient receptor showed defective mammary gland morphogenesis during pregnancy. This was associated with decreas ...[more]

PMID: 25117682

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Project description:BackgroundMorphogenesis results from the coordination of distinct cell signaling pathways controlling migration, differentiation, apoptosis, and proliferation, along stem/progenitor cell dynamics. To decipher this puzzle, we focused on epithelial-mesenchymal transition (EMT) "master genes". EMT has emerged as a unifying concept, involving cell-cell adhesion, migration and apoptotic pathways. EMT also appears to mingle with stemness. However, very little is known on the physiological role and relevance of EMT master-genes. We addressed this question during mammary morphogenesis. Recently, a link between Slug/Snai2 and stemness has been described in mammary epithelial cells, but EMT master genes actual localization, role and targets during mammary gland morphogenesis are not known and we focused on this basic question.Methodology/principal findingsUsing a Slug-lacZ transgenic model and immunolocalization, we located Slug in a distinct subpopulation covering about 10-20% basal cap and duct cells, mostly cycling cells, coexpressed with basal markers P-cadherin, CK5 and CD49f. During puberty, Slug-deficient mammary epithelium exhibited a delayed development after transplantation, contained less cycling cells, and overexpressed CK8/18, ER, GATA3 and BMI1 genes, linked to luminal lineage. Other EMT master genes were overexpressed, suggesting compensation mechanisms. Gain/loss-of-function in vitro experiments confirmed Slug control of mammary epithelial cell luminal differentiation and proliferation. In addition, they showed that Slug enhances specifically clonal mammosphere emergence and growth, cell motility, and represses apoptosis. Strikingly, Slug-deprived mammary epithelial cells lost their potential to generate secondary clonal mammospheres.Conclusions/significanceWe conclude that Slug pathway controls the growth dynamics of a subpopulation of cycling progenitor basal cells during mammary morphogenesis. Overall, our data better define a key mechanism coordinating cell lineage dynamics and morphogenesis, and provide physiological relevance to broadening EMT pathways.

Dataset Information

Integrin ?v?3 drives slug activation and stemness in the pregnant and neoplastic mammary gland.

Publications

Integrin αvβ3 drives slug activation and stemness in the pregnant and neoplastic mammary gland.

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