Data from Tumor α<sub>v</sub>β<sub>3</sub> Integrin Is a Therapeutic Target for Breast Cancer Bone Metastases

Abstract

<div>Abstract<p>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 α<sub>v</sub>β<sub>3</sub> 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 α<sub>v</sub>β<sub>3</sub> integrin would prevent bone metastasis formation. We first showed that, compared with mock-transfected cells, the i.v. inoculation of α<sub>v</sub>β<sub>3</sub>-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 α<sub>v</sub>β<sub>3</sub>-overexpressing transfectants into the tibial bone marrow cavity did not however enhance skeletal tumor burden and bone destruction, suggesting that α<sub>v</sub>β<sub>3</sub> controls earlier events during bone metastasis formation. We next examined whether a nonpeptide antagonist of α<sub>v</sub>β<sub>3</sub> (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, α<sub>v</sub>β<sub>3</sub>-expressing tumor cells <i>in vivo</i> and blocked tumor cell invasion <i>in vitro</i>. Overall, our data show that tumor α<sub>v</sub>β<sub>3</sub> integrin stands as a therapeutic target for the prevention of skeletal metastases. [Cancer Res 2007;67(12):5821–30]</p></div>