BMP-4 enhances epithelial mesenchymal transition and cancer stem cell properties of breast cancer cells via Notch signaling

Abstract

Bone morphogenetic protein (BMP) signaling and Notch signaling play important roles in tumorigenesis in various organs and tissues, including the breast. BMP-4 enhanced epithelial mesenchymal transition (EMT) and stem cell properties in both mammary epithelial cell line and breast carcinoma cell line. BMP-4 increased the expression of EMT biomarkers, such as fibronectin, laminin, N-cadherin, and Slug. BMP-4 also activated Notch signaling in these cells and increased the sphere forming efficiency of the non-transformed mammary epithelial cell line MCF-10A. In addition, BMP-4 upregulated the sphere forming efficiency, colony formation efficiency, and the expression of cancer stem cell markers, such as Nanog and CD44, in the breast carcinoma cell line MDA-MB-231. Inhibition of Notch signaling downregulated EMT and stem cell properties induced by BMP-4. Down-regulation of Smad4 using siRNA impaired the BMP-4-induced activation of Notch signaling, as well as the BMP-4-mediated EMT. These results suggest that EMT and stem cell properties are increased in mammary epithelial cells and breast cancer cells through the activation of Notch signaling in a Smad4-dependent manner in response to BMP-4.

Targeting cancer stem cell pathways for cancer therapy

“…200 In addition, KLF4 and BMP4 also increase Notch1 and Jagged 1 in breast CSCs to regulate cell migration and invasion. 201,202 BRCA1 is a key regulator of breast cancer cell differentiation; however, it is localized to a conserved intronic enhancer region within the Notch ligand Jagged 1 gene to maintain the stemness of breast CSCs. 203 Similarly, increased Gli3 also promotes cell proliferation and invasion in oral SCC by increasing Notch2.…”

Skeleton-vasculature chain reaction: a novel insight into the mystery of homeostasis

“… 72 Dll4–Notch integration triggers modulated angiocrine secretion of Noggin by ECs, which is an antagonist of growth factors collectively known as BMPs. 73 Therefore, Noggin regulates the recruitment and differentiation of osteoprogenitor cells, thus promoting bone formation and accelerating the hypertrophy and maturation of chondrocytes in the adjacent growth plate. 74 Ramasamy et al once conducted a study on mice with an EC-specific deficiency of Fbxw7 (which mediates polyubiquitination and proteasomal degradation of active Notch); these mice were characterized by overactivation of Notch in ECs.…”

Balancing STAT Activity as a Therapeutic Strategy

“…Likewise, the emergence of CSC properties, which are often defined experimentally as using tumorsphere- or tumor-initiating assays, frequently occur concomitantly with a mesenchymal phenotype [156,157,158,159,160,161,162,163]. STAT3 has been identified as an essential driver of the de novo reprogramming to a CSC state through activation of Sox2, Nanog, and Oct4 [164,165,166,167,168,169,170].…”