Research ArticleCancer

ABL kinases promote breast cancer osteolytic metastasis by modulating tumor-bone interactions through TAZ and STAT5 signaling

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Sci. Signal.  02 Feb 2016:
Vol. 9, Issue 413, pp. ra12
DOI: 10.1126/scisignal.aad3210

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Metastatic breast tumors break down bone

Most breast cancer cells activate the breakdown of bone to promote metastases. Wang et al. found that the ABL kinase isoforms ABL1 and ABL2 enhanced the ability of breast cancer cells to invade and break down bone in mice. In breast cancer cells, the ABL kinases activated the transcriptional coactivator TAZ and the transcription factor STAT5, which triggered the transcription of genes encoding factors that activate osteoclasts (cells that break down bone) and those that enhance the survival of breast cancer cells in the bone microenvironment. An ABL-specific inhibitor decreased bone metastasis in mice, thus suggesting that blocking ABL kinase activity could prevent breast cancer cells from promoting bone metastasis.

Abstract

Bone metastases occur in up to 70% of advanced breast cancer. For most patients with breast cancer, bone metastases are predominantly osteolytic. Interactions between tumor cells and stromal cells in the bone microenvironment drive osteolytic bone metastasis, a process that requires the activation of osteoclasts, cells that break down bone. We report that ABL kinases promoted metastasis of breast cancer cells to bone by regulating the crosstalk between tumor cells and the bone microenvironment. ABL kinases protected tumor cells from apoptosis induced by TRAIL (TNF-related apoptosis-inducing ligand), activated the transcription factor STAT5, and promoted osteolysis through the STAT5-dependent expression of genes encoding the osteoclast-activating factors interleukin-6 (IL-6) and matrix metalloproteinase 1 (MMP1). Furthermore, in breast cancer cells, ABL kinases increased the abundance of the Hippo pathway mediator TAZ and the expression of TAZ-dependent target genes that promote bone metastasis. Knockdown of ABL kinases or treatment with ABL-specific allosteric inhibitor impaired osteolytic metastasis of breast cancer cells in mice. These findings revealed a role for ABL kinases in regulating tumor-bone interactions and provide a rationale for using ABL-specific inhibitors to limit breast cancer metastasis to bone.

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