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Tumor _vß₃ Integrin Is a Therapeutic Target for Breast Cancer Bone Metastases

¹ Institut National de la Sante et de la Recherche Medicale, UMR 664, IFR62, Lyon, France; ² Centre Léon Bérard, Lyon, France; ³ Université Lyon 1, Villeurbanne, France; ⁴ Proskelia, a Galapagos Co., Romainville, France; and ⁵ Departments of Cell Biology and Orthopedics, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Philippe Clézardin, Institut National de la Sante et de la Recherche Medicale, UMR664, Faculté de Médecine Laennec, Rue Guillaume Paradin, 69372 Lyon Cedex 08, France. Phone: 33-4-78-78-57-37; Fax: 33-4-78-77-87-72; E-mail: clezardin{at}lyon.inserm.fr.

In breast cancer bone metastasis, tumor cells stimulate osteoclast-mediated bone resorption, and bone-derived growth factors released from resorbed bone stimulate tumor growth. The _vß₃ integrin is an adhesion receptor expressed by breast cancer cells and osteoclasts. It is implicated in tumor cell invasion and osteoclast-mediated bone resorption. Here, we hypothesized that the therapeutic targeting of tumor _vß₃ integrin would prevent bone metastasis formation. We first showed that, compared with mock-transfected cells, the i.v. inoculation of _vß₃-overexpressing MDA-MB-231 breast cancer cells in animals increased bone metastasis incidence and promoted both skeletal tumor burden and bone destruction. The direct inoculation of _vß₃-overexpressing transfectants into the tibial bone marrow cavity did not however enhance skeletal tumor burden and bone destruction, suggesting that _vß₃ controls earlier events during bone metastasis formation. We next examined whether a nonpeptide antagonist of _vß₃ (PSK1404) exhibits meaningful antitumor effects in experimental breast and ovarian cancer bone metastasis. A continuous PSK1404 treatment, which inhibited osteoclast-mediated bone resorption in an animal model of bone loss, substantially reduced bone destruction and decreased skeletal tumor burden. Importantly, a short-term PSK1404 treatment that did not inhibit osteoclast activity also decreased skeletal tumor burden and bone destruction. This dosing regimen caused a profound and specific inhibition of bone marrow colonization by green fluorescent protein, _vß₃-expressing tumor cells in vivo and blocked tumor cell invasion in vitro. Overall, our data show that tumor _vß₃ integrin stands as a therapeutic target for the prevention of skeletal metastases. [Cancer Res 2007;67(12):5821–30]

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