Abstract
Bone morphogenetic protein 2 (BMP-2) has been reported to facilitate epithelial-to-mesenchymal transition (EMT) and bone metastasis in breast cancer xenograft models. To investigate the role of BMP-2 in the development of breast cancer stem cells (BCSCs), and to further elucidate the mechanisms underlying its influence on breast cancer metastasis, we conducted a comprehensive molecular study using breast cancer cell lines and clinical samples. Our results showed that downregulation of Rb by BMP-2 was associated with ubiquitin-mediated degradation activated by phosphorylation of Rb via the PI3K/AKT signal pathway. In addition, the Smad signaling pathways are implicated in upregulation of CD44 protein expression by BMP-2. It was suggested that cross-talk exists between Rb and CD44 signaling pathways, as recombinant human BMP-2 (rhBMP-2) was found to regulate CD44 expression partly through Rb signals. In clinical tissues, BMP-2 was positively and negatively correlated with CD44 and Rb expression, respectively. Based on the in vitro and in vivo results, we have established an integrated mechanism by which rhBMP-2 induces EMT and stemness of breast cancer cells via the Rb and CD44 signaling pathways, which then contribute to breast cancer metastasis. These findings may be helpful for developing new strategies for the treatment and prognosis of advanced breast cancer.
Highlights
Breast cancer is a leading cause of cancer deaths among women worldwide, second only to lung cancer;[1] metastasis is the main cause for breast cancer related deaths.[2,3]The concept that cancer stem cells (CSCs) drive cancer formation and progression has recently gained attention
We found that recombinant human Bone morphogenetic proteins (BMPs)-2 (rhBMP-2) induced elongated and the metastatic phenotype of clinical breast cancer, we morphologic changes in all three breast cancer cell lines
As actin cytoskeleton reorganization is considered another characteristic of epithelial-to-mesenchymal transition (EMT), we used atomic force microscopy (AFM) and fluorescence microscopy to observe the structure of actin cytoskeleton in rhBMP-2-induced MCF-7 cells
Summary
The concept that cancer stem cells (CSCs) drive cancer formation and progression has recently gained attention. Studies have shown that breast cancer stem cells (BCSCs, marked as CD44+/CD24−) promote tumor progression and exhibit enhanced invasive properties to favor distant metastasis in patients.[4,5]. BMP-2 was reported to facilitate epithelial-to-mesenchymal transition (EMT)[6] and promote the motility and invasiveness of breast cancer cells in vitro and in mouse xenograft model.[7,8] A recent study reported that the BMP-2 pathway can be activated by pollutants exposure, and contributes to stem cell transformation and breast cancer initiation.[9] the mechanisms by which BMP-2 promotes
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