Breast cancer cells obtain an osteomimetic featureviaepithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction

Abstract

Bone is one of the most common organs of breast cancer metastasis. Cancer cells that mimic osteoblasts by expressing bone matrix proteins and factors have a higher likelihood of metastasizing to bone. However, the molecular mechanisms of osteomimicry formation of cancer cells remain undefined. Herein, we identified a set of bone-related genes (BRGs) that are ectopically co-expressed in primary breast cancer tissues and determined that osteomimetic feature is obtained due to the osteoblast-like transformation of epithelial breast cancer cells that have undergone epithelial-mesenchymal transition (EMT) followed by bone morphogenetic protein-2 (BMP2) stimulation. Furthermore, we demonstrated that breast cancer cells that transformed into osteoblast-like cells with high expression of BRGs showed enhanced chemotaxis, adhesion, proliferation and multidrug resistance in an osteoblast-mimic bone microenvironment in vitro. During these processes, runt-related transcription factor 2 (RUNX2) functioned as a master mediator by suppressing or activating the transcription of BRGs that underlie the dynamic antagonism between the TGF-β/SMAD and BMP/SMAD signaling pathways in breast cancer cells. Our findings suggest a novel mechanism of osteomimicry formation that arises in primary breast tumors, which may explain the propensity of breast cancer to metastasize to the skeleton and contribute to potential strategies for predicting and targeting breast cancer bone metastasis and multidrug resistance.

Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance

“…2016 ). Tan and coworkers ( Tan et al . 2016 ) showed that breast cancer cells with induced EMT exhibited an elevated level of bone-related genes (BRGs) and osteoblast-like features in an exposure to BMP-2.…”

Bone Marrow Adipocytes, Adipocytokines, and Breast Cancer Cells: Novel Implications in Bone Metastasis of Breast Cancer

“…Breast cancer cells can undergo osteomimicry after EMT and express factors that are the main mediators of bone remodeling typically found in osteoblasts ( 95 ). An osteomimicry profile is characterized by an increased expression of bone sialoprotein (BSP), osteopontin (OPN), osteoprotegerin (OPG), osteonectin (ON), cadherin 11 (CDH11), transcription factor runt-related transcription factor 2 (Runx2) ( 96 ), etc. These bone-related genes (BRGs) are highly expressed in bone metastatic cancer cells, compared to those cells metastasized in other organs, and their expression is regulated by the transcription factor Runx2 that acts as a master mediator ( 97 ).…”

Key Factors in Breast Cancer Dissemination and Establishment at the Bone: Past, Present and Future Perspectives

“…Breast cancer cells themselves can display an osteoblast-like phenotype by expressing bone matrix proteins such as bone sialoprotein (BSP), osteopontin (OPN), OPG and osteoblast-specific cadherins [91][92][93]. Breast cancer cells with induced epithelial-to-mesenchymal transition (EMT) exhibited an elevated level of bone-related genes (BRGs) and osteoblast-like features when exposed to BMP-2.…”

“…Interestingly, the cells were also more resistant to chemotherapy [93]. The BMP antagonist Noggin reversed these effects, as did knockdown of runt-related transcription factor 2 (RUNX2), which regulates bone remodelling and osteogenic differentiation [68,93,94]. This 'bone signature' induced by BMPs may be one of the reasons breast cancer cells home to bone tissue.…”