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

Abstract

BackgroundThe transforming growth factor (TGF)-β superfamily comprises cytokines such as TGF-β and Bone Morphogenetic Proteins (BMPs), which have a critical role in a multitude of biological processes. In breast cancer, high levels of TGF-β are associated with poor outcome, whereas inhibition of TGF-β-signaling reduces metastasis. In contrast, BMP-7 inhibits bone metastasis of breast cancer cells.MethodsIn this study, we investigated the effect of BMP-7 on TGF-β-induced invasion in a 3 dimensional invasion assay.ResultsBMP-7 inhibited TGF-β-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-β-induced invasion, we analyzed invasion-related genes. BMP-7 inhibited TGF-β-induced expression of integrin αvβ3 in the spheroids. Moreover, targeting of integrins by a chemical inhibitor or knockdown of integrin β3 negatively affected TGF-β-induced invasion. On the other hand, overexpression of integrin β3 counteracted the inhibitory effect of BMP7 on TGF-β-induced invasion.ConclusionThus, BMP-7 may exert anti-invasive actions by inhibiting TGF-β-induced expression of integrin β3.Electronic supplementary materialThe online version of this article (doi:10.1007/s13402-011-0058-0) contains supplementary material, which is available to authorized users.

GTF2IRD1 on chromosome 7 is a novel oncogene regulating the tumor‐suppressor gene TGFβR2 in colorectal cancer

“…Recently, some reports have focused on the cross‐talk between TGFβ signal and the BMP signaling pathway in the progression of cancers. BMP7 attenuates TGFβ‐mediated tumor suppression in proliferation or invasion in prostate cancer or breast cancer respectively . In our study, GTF2IRD1 downregulated TGFβR2, but upregulated BMPR1b expression in CRC cells, suggesting that the upregulation of BMPR1b by GTF2IRD1 might indirectly decrease TGFβR2 expression, resulting in suppression of TGFβ signal (Figure D).…”

Embedded Spheroids as Models of the Cancer Microenvironment

“…The authors propose that the mechanism of invasion occurs through degradation of collagen fibers, which is supported by confocal reflectance images of the ECM . Imaging remains the most prevalent spheroid characterization method to assess invasion distance, area, or individual invading cells as evident from studies on glioma and breast spheroids. Subsequent modifications that increase the utility of imaging involve the use of other imaging modalities, such as single cell tracking using MRI on iron oxide labeled glioma spheroids .…”

“…The studies employ spheroids of MCF10a derivatives, which modeled tumors of increasing malignant potential . This system allows them to correlate TGF‐β induced invasion with malignant potential, implicate BMP‐7 as an inhibitor of invasion in the post metastatic, but not pre‐malignant MCF10a derivatives, and to quantify the contributions of Smad3, Smad4, MMP‐2 and MMP‐9 in TGF‐β induced invasion . The expression of transcriptional repressors Snail and Slug allows monitoring of the EMT after treatment with TGF‐β .…”

RGD-Binding Integrins in Prostate Cancer: Expression Patterns and Therapeutic Prospects against Bone Metastasis

“…TGF-β upregulates expression of the RGD-binding integrins [137] and there is extensive crosstalk between TGF-β and α v β 3 [138], α v β 5 [139,140], α v β 6 [103,141], and α 5 β 1 [142,143]. TGF-β also regulates EMT, where cells acquire the invasive, migratory phenotype required for metastasis.…”