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J. Biol. Chem., Vol. 282, Issue 5, 3262-3272, February 2, 2007

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Lysyl Oxidase Interacts with Hormone Placental Lactogen and Synergistically Promotes Breast Epithelial Cell Proliferation and Migration^*

Noemi Polgar, Ben Fogelgren, J. Michael Shipley^¶, and Katalin Csiszar¹

From the Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96822, the Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, and the ^¶Division of Pulmonary and Critical Care Medicine, Washington University, St. Louis, Missouri 63110

Lysyl oxidase (LOX), an extracellular amine oxidase, catalyzes the cross-linking of collagen and elastin. LOX has been also shown to play an essential role in promoting the invasive and metastatic potential of breast tumor cells. However, the LOX-interacting factors in these processes are not known. In this study, we identified placental lactogen (PL), a member of the growth hormone/prolactin hormone family, as a LOX-interacting partner using yeast two-hybrid screens. PL is normally only expressed in placental syncytiotrophoblasts, but PL genes are amplified and expressed in a high percentage of invasive ductal breast carcinomas. We confirmed LOX-PL interactions using far Western and solid phase binding assays. In activity assays, PL was not a substrate or inhibitor of LOX. We further demonstrated that PL is expressed in breast tumor epithelial cells and detected LOX-PL interactions by coimmunoprecipitation in invasive breast cancer cells. In MCF-10A normal breast epithelial cells stably expressing LOX, PL, or both, LOX had no effect on cell proliferation, PL alone increased proliferation by 49%, and coexpression of LOX and PL led to a 121% increase in cell proliferation. Unlike in tumor cells, LOX did not induce a more migratory phenotype in MCF-10A cells; nor did PL. However, their coexpression resulted in a 240% increase in cell migration, suggesting that these interactions may be highly relevant to the transition of epithelial cells toward a migratory phenotype during the development and progression of breast carcinoma and a significant role for LOX-PL interactions in epithelial cell behavior.

Received for publication, October 5, 2006 , and in revised form, November 27, 2006.

^* This work was supported by National Institutes of Health Grants AR47713 and G12RR003096. 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 To whom correspondence should be addressed: Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii, 1960 East-West Rd., Biomed T311, Honolulu, HI 96822. Tel.: 808-956-9452; Fax: 808-956-9481; E-mail: Kcsiszar{at}aol.com.

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