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

Abstract

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 b-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 TGFb 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.

Targeting the tumour stroma to improve cancer therapy

“…Osteoblasts themselves might be able to initiate this cycle 172 . In osteoclasts, expression of RUNX2 has been linked in experimental models and patient samples to the upregulation of factors that promote cancer metastasis to the bone, such as the BMPs 173 . Tumour-induced pressure causes increased osteocyte secretions (for example, of CCL5 and MMPs), which promote the growth of prostate cancer-derived bone metastasis in mouse models 174 .…”

MiR-30a regulates the proliferation, migration, and invasion of human osteosarcoma by targeting Runx2

“…Runx2 stimulates the maturation of osteoblasts during bone differentiation [10]. However, its expression is dysregulated in some kinds of cancer, such as bladder urothelial carcinoma, prostate cancer, and osteosarcoma [11][12][13][14][15]. Runx2 is involved in bladder tumor carcinogenesis and aggressiveness [16].…”

RUNX2 promotes breast cancer bone metastasis by increasing integrin α5-mediated colonization

“…GFP-labeled MDA-MB-231 cells with RUNX2-overexpression, RUNX2-overexpression plus ITGA5 knockdown, or the control cells were injected into the left cardiac ventricle (1.0 × 10 6 ) or the cortex of the right tibia (2.0 × 10 5 ) [12] of fiveweek-old Balb/c nude mice. After 24 hours, the mice were sacrificed, and the bone marrow cells were flushed from the femurs and tibias.…”

“…RUNX2 has been found to be highly expressed in breast cancer cell lines with high bone metastatic potential [5][6][7]. The in vitro and in vivo evidence demonstrates that RUNX2 is an important contributor to breast cancer bone metastasis [7,8] due to its contribution to the acquisition of invasive and motility capabilities [4,6,9] and the formation of osteolytic lesions [10][11][12] in the progression of bone metastasis. However, current studies still lack direct clinical evidence of the promotion of bone-specific metastasis of breast cancer by RUNX2, and the mechanism of RUNX2 in breast cancer cell recruitment and adhesion to the bone remains unclear.…”