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J. Biol. Chem., Vol. 282, Issue 43, 31766-31776, October 26, 2007

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Mammary Epithelial-specific Deletion of the Focal Adhesion Kinase Gene Leads to Severe Lobulo-Alveolar Hypoplasia and Secretory Immaturity of the Murine Mammary Gland^*

Tamas Nagy¹, Huijun Wei, Tang-Long Shen, Xu Peng, Chun-Chi Liang, Boyi Gan, and Jun-Lin Guan²

From the Department of Molecular Medicine, Cornell University, Ithaca, New York 14853 and Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109

Integrin-mediated cell adhesion and signaling is required for mammary gland development and functions. As a major mediator of integrin signaling, focal adhesion kinase (FAK) has been implicated to play a role in the survival, proliferation, and differentiation of mammary epithelial cells in previously studies in vitro. To assess the role of FAK in vivo, we created mice in which FAK is selectively deleted in mammary epithelial cells. The mammary gland FAK conditional knock-out (MFCKO) mice are viable, fertile, and macroscopically indistinguishable from the control littermates. In virgin MFCKO mice, mammary ductal elongation is retarded at 5 weeks of age but reaches the full extent by 8 weeks of age compared with the control mice. However, the MFCKO females are unable to nurse their pups due to severe lobulo-alveolar hypoplasia and secretory immaturity during pregnancy and lactation. Analysis of the mammary epithelial cells in MFCKO mice showed reduced Erk phosphorylation, expression of cyclin D1, and a corresponding decrease in proliferative capability compared with the littermate controls. In addition, phosphorylation of STAT5 and expression of whey acidic protein are significantly reduced in the mammary glands of MFCKO mice, suggesting defective secretory maturation in these mice. Therefore, the combination of the severe lobulo-alveolar hypoplasia and defective secretory differentiation is responsible for the inability of the MFCKO females to nurse their pups. Together, these results provide strong support for a role of FAK in the mammary gland development and function in vivo.

Received for publication, July 2, 2007 , and in revised form, August 15, 2007.

^* This research was supported in part by National Institutes of Health Grant GM48050 (to J.-L. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by United States Department of Defense Predoctoral Traineeship Award W81XWH-04-1-0400).

² To whom correspondence should be addressed: Division of Molecular Medicine and Genetics, Dept. of Internal Medicine, Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109. Tel.: 734-615-4936; Fax: 734-615-2506; E-mail: jlguan{at}umich.edu.

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