BMP-2 induces EMT and breast cancer stemness through Rb and CD44

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.

Incorporating MicroRNA into Molecular Phenotypes of Circulating Tumor Cells Enhances the Prognostic Accuracy for Patients with Metastatic Breast Cancer

“…Second, according to our results, CTC‐specific miR‐106b was expressed at a higher level in mesenchymal‐like CTCs that highly expressed vimentin, suggesting that there is a coordination between miR‐106b and EMT‐related phenotypes of CTCs. Third, mechanically, our previous study demonstrated that miR‐106b determines the effect of transforming growth factor β, a key EMT inducer, on the tumor behavior of breast cancer cells by targeting RB . Several studies have also demonstrated that a variety of genes were identified as the target of miR‐106b including caspase‐7 , PTEN , and Smad7 , which contribute to miR‐106b‐mediated EMT of cancer cells.…”

“…First, molecular phenotypes of CTCs were associated with various behavior of cancer cells including anoikis resistance metastasis and therapeutic resistance. It has been reported that miR‐106b promotes anoikis resistance and EMT processes in breast cancer cells by targeting RB and Snail gene . Acquisition of a more malignant phenotype for CTC might easily explain the resistance to elimination strategies such as chemotherapy, local antigrowth signaling, and immune attack by the host.…”

The Dual Role of Bone Morphogenetic Proteins in Cancer

“…Therefore, conclusions based on simply one cell line may be too straightforward, so diverse cancer cell lines or different types of tumors should be used; the suitable consensus is that BMPs and their involvement might act as both tumor promoters and oncogenes in cancer development ( Figure 3 ). 34 , 35 , 36 , 37 , 38 , 39 Although there is no definitive correlation between BMPs and the development of tumorigenesis, a large number of studies indicate a positive effect of BMPs on cancer development. Therefore, BMPs should be paid careful attention for cancer patient treatment.…”

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

“…In addition to WNT/β-catenin and JAK/STAT3 signaling, PI3K/AKT signaling is induced by CD44. The generation of breast CSCs can involve a BMP-2–mediated degradation of Rb, leading to SMAD activation and increased CD44 expression 60 . CD44s and CD44v isoforms are prognostic markers for several cancers, and CD44 is used in targeted cancer therapy using anti-CD44 antibodies and CD44 antagonizing peptides 61 .…”