Integrin αvβ3 Drives Slug Activation and Stemness in the Pregnant and Neoplastic Mammary Gland

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 decreased MaSC expansion, clonogenicity, and expression of Slug, a master regulator of MaSCs. Surprisingly, αvβ3-deficient mice displayed normal development of the virgin gland with no effect on luminal progenitors. Transforming growth factor β2 (TGF-β2) induced αvβ3 expression, enhancing Slug nuclear accumulation and MaSC clonogenicity. In human breast cancer cells, αvβ3 was necessary and sufficient for Slug activation, tumorsphere formation, and tumor initiation. Thus, pregnancy-associated MaSCs require a TGF-β2/αvβ3/Slug pathway, which may contribute to breast cancer progression and stemness. [Display omitted] •Pregnancy increases expression of the integrin αvβ3 in mammary stem cells (MaSCs)•αvβ3 is critical for initiating alveologenesis and remodeling during pregnancy•αvβ3 mediates pregnancy-induced MaSC expansion, clonogenicity, and Slug expression•In breast cancer, αvβ3 similarly regulates Slug expression and stem-like behavior Integrin αvβ3 has been linked to breast cancer progression, but its role in epithelial development is unclear. Desgrosellier et al. now show that αvβ3 is critical for adult mammary stem cells during pregnancy by mediating epithelial remodeling. This may be related to αvβ3-mediated stem-like behavior in cancers.