Background:
ITGBL1 was found high expressed in breast cancer tissues, and related to metastasis of breast cancer in our previous study. Due to the evidence that ITGBL1 was reported over-expressed in high bone-metastatic breast cancer cells and there are three binding motifs of Runx2 in its promoter, ITGBL1 might involve in bone metastasis of breast cancer.
Aim:
To clarify the role and mechanism of ITGBL1 in bone metastasis of breast cancer.
Methods:
The correlation of ITGBL1 and “osteomimetic” markers were calculated based on the previous microarray data and GOBO database. ChIP and dual luciferase reporter assays were used to confirm the regulation of Runx2 to ITGBL1. The clinical significance of ITGBL1 in bone metastasis was determined using 88 breast cancers and two published datasets. We investigated whether ITGBL1 could facilitate cancer cells attaching, colonizing and proliferating in a bone-mimicking microenvironment. A co-culture system of cancer cells and osteoclast precursor was developed to determine the role of ITGBL1 in osteoclast differentiation. Moreover, we confirmed TGF-β pathway mediating the function of ITGBL1 in chemotactic responses to bone and osteoclasts activation.
Results:
ITGBL1 was confirmed co-expressed with a set of bone metastasis related genes and regulated by Runx2. In vivo, breast cancer with high ITGBL1 level was prone to metastasize to bone. In vitro, ITGBL1 promoted cancer cells homing to bone, facilitated cancer cells surviving and growing in bone microenvironment, and stimulated osteoclast formation. In addition, decreased ITGBL1 reduced the bone metastasis potential by Runx2. Moreover, TGF-β pathway was confirmed to mediate the function of ITGBL1 in bone metastasis of breast cancer.
Conclusions:
ITGBL1, as a target gene of Runx2, could increase the secretory TGF-βs, and therefore, accelerate bone metastasis of breast cancer by promoting cancer cells homing to bone, facilitating cancer cells surviving in bone microenvironment, and stimulating osteoclast formation.