Breast cancer cells obtain an osteomimetic feature via epithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction.
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.
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
Cong-Cong
CC
Tan
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
Gui-Xi
GX
Li
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
Li-Duan
LD
Tan
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
Xin
X
Du
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.|Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
Xiao-Qing
XQ
Li
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
Rui
R
He
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.|Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
Qing-Shan
QS
Wang
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.|Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
Yu-Mei
YM
Feng
D000970:Antineoplastic Agents / Q000494:pharmacology; D000067558:Biological Mimicry; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic; D059016:Tumor Microenvironment; D015854:Up-Regulation
D000970:Antineoplastic Agents; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human
BMP2/RUNX2 signaling pathway; breast cancer bone metastasis; cancer-associated fibroblast; epithelial-mesenchymal transition; osteomimicry