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Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer

Departments of ¹ Endocrinology, ² Urology, ³ Molecular Cell Biology, and ⁴ Pathology, Leiden University Medical Center, Leiden, the Netherlands; ⁵ Departments of Clinical Research and Urology, University of Bern, Inselspital, Bern, Switzerland; ⁶ Centre René Huguenin and Institut National de la Sante et de la Recherche Medicale, Research Unit 735, St. Cloud, France; ⁷ Institut National de la Sante et de la Recherche Medicale, Research Unit 664, Laennec School of Medicine, Lyon, France; and ⁸ Department of Anatomy, School of Medicine, Zagreb, Croatia

Requests for reprints: Jeroen T. Buijs, Department of Endocrinology, Leiden University Medical Center, C4-R, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. Phone: 31-71-5266652; Fax: 31-71-5248136; E-mail: J.T.Buijs{at}lumc.nl.

Bone morphogenetic protein 7 (BMP7) counteracts the physiological epithelial-to-mesenchymal transition (EMT), a process that is indicative of epithelial plasticity. Because EMT is involved in cancer, we investigated whether BMP7 plays a role in breast cancer growth and metastasis. In this study, we show that decreased BMP7 expression in primary breast cancer is significantly associated with the formation of clinically overt bone metastases in patients with 10 years of follow-up. In line with these clinical observations, BMP7 expression is inversely related to tumorigenicity and invasive behavior of human breast cancer cell lines. Moreover, BMP7 decreased the expression of vimentin, a mesenchymal marker associated with invasiveness and poor prognosis, in human MDA-MB-231 (MDA-231)-B/Luc⁺ breast cancer cells under basal and transforming growth factor-ß (TGF-ß)–stimulated conditions. In addition, exogenous addition of BMP7 to TGF-ß–stimulated MDA-231 cells inhibited Smad-mediated TGF-ß signaling. Furthermore, in a well-established bone metastasis model using whole-body bioluminescent reporter imaging, stable overexpression of BMP7 in MDA-231 cells inhibited de novo formation and progression of osteolytic bone metastases and, hence, their metastatic capability. In line with these observations, daily i.v. administration of BMP7 (100 µg/kg/d) significantly inhibited orthotopic and intrabone growth of MDA-231-B/Luc⁺ cells in nude mice. Our data suggest that decreased BMP7 expression during carcinogenesis in the human breast contributes to the acquisition of a bone metastatic phenotype. Because exogenous BMP7 can still counteract the breast cancer growth at the primary site and in bone, BMP7 may represent a novel therapeutic molecule for repression of local and bone metastatic growth of breast cancer. [Cancer Res 2007;67(18):8742–51]

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