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Dev Cell. 2014 Aug 11;30(3):295-308. doi: 10.1016/j.devcel.2014.06.005.

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

Author information

1
Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jdesgrosellier@ucsd.edu.
2
Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
3
Division of Hematology-Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

Abstract

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.

PMID:
25117682
PMCID:
PMC4147869
DOI:
10.1016/j.devcel.2014.06.005
[Indexed for MEDLINE]
Free PMC Article

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