BMP-7 inhibits TGF-β-induced invasion of breast cancer cells through inhibition of integrin β3 expression

The transforming growth factor (TGF)-beta superfamily comprises cytokines such as TGF-beta and Bone Morphogenetic Proteins (BMPs), which have a critical role in a multitude of biological processes. In breast cancer, high levels of TGF-beta are associated with poor outcome, whereas inhibition of TGF-beta-signaling reduces metastasis. In contrast, BMP-7 inhibits bone metastasis of breast cancer cells. In this study, we investigated the effect of BMP-7 on TGF-beta-induced invasion in a 3 dimensional invasion assay. BMP-7 inhibited TGF-beta-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-beta-induced invasion, we analyzed invasion-related genes. BMP-7 inhibited TGF-beta-induced expression of integrin alpha(v)beta(3) in the spheroids. Moreover, targeting of integrins by a chemical inhibitor or knockdown of integrin beta(3) negatively affected TGF-beta-induced invasion. On the other hand, overexpression of integrin beta(3) counteracted the inhibitory effect of BMP7 on TGF-beta-induced invasion. Thus, BMP-7 may exert anti-invasive actions by inhibiting TGF-beta-induced expression of integrin beta(3).