BMP-7 inhibits TGF-ß-induced invasion of breast cancer cells through inhibition of integrin ß(3) expression.

ABSTRACT

BACKGROUND: The transforming growth factor (TGF)-ß superfamily comprises cytokines such as TGF-ß and Bone Morphogenetic Proteins (BMPs), which have a critical role in a multitude of biological processes. In breast cancer, high levels of TGF-ß are associated with poor outcome, whereas inhibition of TGF-ß-signaling reduces metastasis. In contrast, BMP-7 inhibits bone metastasis of breast cancer cells. METHODS: In this study, we investigated the effect of BMP-7 on TGF-ß-induced invasion in a 3 dimensional invasion assay. RESULTS: BMP-7 inhibited TGF-ß-induced invasion of the metastatic breast cancer cell line MCF10CA1a, but not of its premalignant precursor MCF10AT in a spheroid invasion model. The inhibitory effect appears to be specific for BMP-7, as its closest homolog, BMP-6, did not alter the invasion of MCF10CA1a spheroids. To elucidate the mechanism by which BMP-7 inhibits TGF-ß-induced invasion, we analyzed invasion-related genes. BMP-7 inhibited TGF-ß-induced expression of integrin α(v)ß(3) in the spheroids. Moreover, targeting of integrins by a chemical inhibitor or knockdown of integrin ß(3) negatively affected TGF-ß-induced invasion. On the other hand, overexpression of integrin ß(3) counteracted the inhibitory effect of BMP7 on TGF-ß-induced invasion. CONCLUSION: Thus, BMP-7 may exert anti-invasive actions by inhibiting TGF-ß-induced expression of integrin ß(3).