Bone sialoprotein‐αvβ3 integrin axis promotes breast cancer metastasis to the bone

Abstract

The underlying mechanisms of breast cancer cells metastasizing to distant sites are complex and multifactorial. Bone sialoprotein (BSP) and αvβ3 integrin were reported to promote the metastatic progress of breast cancer cells, particularly metastasis to bone. Most theories presume that BSP promotes breast cancer metastasis by binding to αvβ3 integrin. Interestingly, we found the αvβ3 integrin decreased in BSP silenced cells (BSPi), which have weak ability to form bone metastases. However, the relevance of their expression in primary tumor and the way they participate in metastasis are not clear. In this study, we evaluated the relationship between BSP, αvβ3 integrin levels, and the bone metastatic ability of breast cancer cells in patient tissues, and the data indicated that the αvβ3 integrin level is closely correlated to BSP level and metastatic potential. Overexpression of αvβ3 integrin in cancer cells could reverse the effect of BSPi in vitro and promote bone metastasis in a mouse model, whereas knockdown of αvβ3 integrin have effects just like BSPi. Moreover, The Cancer Genome Atlas data and RT‐PCR analysis have also shown that SPP1, KCNK2, and PTK2B might be involved in this process. Thus, we propose that αvβ3 integrin is one of the downstream factors regulated by BSP in the breast cancer‐bone metastatic cascade.

A Potential Role of RUNX2- RUNT Domain in Modulating the Expression of Genes Involved in Bone Metastases: An In Vitro Study with Melanoma Cells

“…The re-expression of RUNT by transfecting KO cells with RUNX2 expression vectors restored cells' ability to migrate and invade bone fragments. This finding supports the transcriptional role of the RUNT domain in binding its downstream target genes, such as IBSP and SPP1, which are involved in bone metastasis promotion [45,46]. As discussed above, we observed reduced expression of SPP1 in RUNX2 KO cells.…”

The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment

“…Consistent with their roles in osteogenesis, SPP1 and BSP have been implicated in bone malignancy (16). However, while these proteins were initially thought to be expressed only during bone morphogenesis, both were subsequently shown to be broadly expressed in human epithelial carcinomas, including but not limited to breast (83,84), lung (85,86), prostate (87), liver (88), pancreas (89) and colon (87,90), where their pathophysiological roles have recently been thoroughly reviewed (16,91). Furthermore, CAFs have been shown to produce and secrete SPP1, which contributes to melanoma tumor growth (92).…”

Switching Homes: How Cancer Moves to Bone

“…This process is obviously very complex, but many molecular mediators have been identified and characterised. A key player is αvβ3, an integrin that is well known for mediating the adhesion of osteoclasts to the bone matrix [26], which has been shown to favour bone homing and metastasis when expressed in breast cancer cells [97][98][99][100][101]. Similar actions have been proposed for very late antigen (VLA)-4, which interacts with vascular cell adhesion molecule (VCAM)-1, constitutively expressed in bone marrow endothelial and stromal cells [102].…”