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Breast cancer metastasis to bone is a multistep process requiring attachment of tumor cells to the bone and bone marrow environment. The precise adhesion molecules involved in skeletal homing of breast cancer to bone are unknown but likely include integrins. We investigated the expression of vitronectin receptor (αvβ3) by breast cancer cells residing in bone because this heterodimer mediates osteoclast-bone recognition. We used immunohistochemistry and in situ hybridization in a systematic study of 22 bone biopsies containing breast cancer metastases and available samples of corresponding primary tumors and normal breast and compared αvβ3, αvβ1 and αvβ5 integrin expression. The results showed that αvβ3 was strongly expressed by normal breast epithelium and was decreased in some and strongly expressed in other primary invasive breast carcinomas. In contrast, this integrin heterodimer was abundant in all breast cancer cells metastatic to bone. In situ hybridization revealed high levels of steady-state mRNA corresponding to sites of protein expression; αvβ1 was weakly expressed in both primary and metastatic tumors, and αvβ5 was not detected. Our results showed an overexpression of αvβ3 by bone-residing breast cancer cells and suggest either subclonal selection of αvβ3-expressing tumor cell populations or upregulation of αvβ3 in the bone microenvironment.