ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (16), p.3302-3313
• Main Authors: Li, Xiao-Qing, Du, Xin, Li, Dong-Mei, Kong, Peng-Zhou, Sun, Yan, Liu, Pei-Fang, Wang, Qing-Shan, Feng, Yu-Mei
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - genetics; Cells, Cultured; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Integrin beta1 - genetics; Integrin beta1 - metabolism; Kaplan-Meier Estimate; Mice, Inbred BALB C; Mice, SCID; Osteoblasts - metabolism; Osteogenesis - genetics; Osteolysis - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction - genetics; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-0240

Bone metastasis affects more than 70% of advanced breast cancer patients, but the molecular mechanisms of this process remain unclear. Here, we present clinical and experimental evidence to clarify the role of the integrin β-like 1 (ITGBL1) as a key contributor to bone metastasis of breast cancer. In an in vivo model system and in vitro experiments, ITGBL1 expression promoted formation of osteomimetic breast cancers, facilitating recruitment, residence, and growth of cancer cells in bone microenvironment along with osteoclast maturation there to form osteolytic lesions. Mechanistic investigations identified the TGFβ signaling pathway as a downstream effector of ITGBL1 and the transcription factor Runx2 as an upstream activator of ITGBL1 expression. In support of these findings, we also found that ITGBL1 was an essential mediator of Runx2-induced bone metastasis of breast cancer. Overall, our results illuminate how bone metastasis occurs in breast cancer, and they provide functional evidence for new candidate biomarkers and therapeutic targets to identify risk, to prevent, and to treat this dismal feature of advanced breast cancer.