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

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