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J. Biol. Chem., Vol. 283, Issue 12, 7616-7627, March 21, 2008

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Protein Kinase C Mediates Polymeric Fibronectin Assembly on the Surface of Blood-borne Rat Breast Cancer Cells to Promote Pulmonary Metastasis^*

Lynn Huang, Hung-Chi Cheng, Richard Isom, Chia-Sui Chen, Roy A. Levine, and Bendicht U. Pauli¹

From the Cancer Cell Biology Laboratories, Department of Molecular Medicine, Cornell University, Ithaca, New York 14853 and Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan

Malignant breast cancer cells that have entered the blood circulation from primary mammary fat pad tumors or are grown in end-over-end suspension culture assemble a characteristic, multi-globular polymeric fibronectin (polyFn) coat on their surfaces. Surface polyFn is critical for pulmonary metastasis, presumably by facilitating lung vascular arrest via endothelial dipeptidylpeptidase IV (CD26). Here, we show that cell-surface polyFn assembly is initiated by the state of suspension, is dependent upon the synthesis and secretion of cellular Fn, and is augmented in a dose- and time-dependent manner by plasma Fn. PolyFn assembly is regulated by protein kinase C (PKC), which translocates rapidly and in increasing amounts from the cytosol to the plasma membrane and is phosphorylated. PolyFn assembly is impeded by select inhibitors of this kinase, i.e. bisindolylmaleimide I, Ro-32-0432, Gö6983, and Rottlerin, by the phorbol 12-myristate 13-acetate-mediated and time-dependent loss of PKC protein and decreased plasma membrane translocation, and more specifically, by stable transfection of lung-metastatic MTF7L breast cancer cells with small interfering RNA-PKC and dominant-negative PKC constructs (e.g. RD-PKC). The inability to assemble a cell surface-associated polyFn coat by knockdown of endogenous Fn or PKC impedes cancer cells from metastasis to the lungs. The present studies identify a novel regulatory mechanism for polyFn assembly on blood-borne breast cancer cells and depict its effect on pulmonary metastasis.

Received for publication, July 16, 2007 , and in revised form, November 28, 2007.

^* This work was supported by grants from the United States Army Department of Defense Breast Cancer Program BC031992 and by the Breast Cancer Coalition of Rochester (to B. U. P.). 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: Dept. of Molecular Medicine, Cornell University, VMC4 #151, Ithaca, NY 14853. Tel.: 607-253-3343; Fax: 607-253-3659; E-mail: bup1{at}cornell.edu.

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