title: Integrin αvβ3 drives slug activation and stemness in the pregnant and neoplastic mammary gland.
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.
authors.affiliation: Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jdesgrosellier@ucsd.edu.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Desgrosellier
authors.affiliation: Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lesperance
authors.affiliation: Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Seguin
authors.affiliation: Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Maricel
authors.initials: M
authors.lastname: Gozo
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Shumei
authors.initials: S
authors.lastname: Kato
authors.affiliation: Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Franovic
authors.affiliation: Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Mayra
authors.initials: M
authors.lastname: Yebra
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Sanford J
authors.initials: SJ
authors.lastname: Shattil
authors.affiliation: Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000172:deficiency / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D011247:Pregnancy; D000071250:Snail Family Transcription Factors; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C509042:Tgfb2 protein, mouse; D014157:Transcription Factors; D053781:Transforming Growth Factor beta2