Bone metastasis is a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer. Breast cancer metastasis to the bone is associated with decreased survival, and patients with bone metastases experience severe pain, pathologic fractures, life-threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. A greater understanding of the mechanisms that promote metastasis to the bone is required to identify actionable targets to treat this disease.
We have uncovered a novel role for the ABL family kinases in the regulation of breast cancer metastasis to the bone. Using next-generation sequencing we found that ABL kinases regulate the expression of multiple genes that modulate tumor-bone interactions. Gene Set Enrichment Analysis (GSEA) of multiple databases revealed that a gene signature consisting of 273 genes important for breast cancer bone metastasis was down-regulated in ABL1/ABL2 knockdown cells. Notably, we showed that inactivation of the ABL kinases elicited down-regulation of the Hippo pathway signature as well as the JAK/STAT and Cytokine/Cytokine Receptor pathway signatures. Among the transcripts that were markedly decreased in ABL1/ABL2 knockdown cells were the Hippo pathway regulator TAZ and the STAT5A transcription factor. Using rescue strategies, we showed that ABL kinases modulated the expression of pro-bone metastasis factors via co-activation of the TAZ and STAT5 transcription networks, and that expression of activated TAZ and STAT5 rescued metastatic activity in ABL1/ABL2-knockdown breast cancer cells in mouse models.
Notably, we found that treatment of tumor-bearing mice with selective allosteric inhibitors targeting the ABL kinases, or silencing ABL1 and ABL2 in breast cancer cells markedly impaired bone metastasis and blocked tumor-induced osteolysis (Figure 1). These findings have far-reaching implications for the treatment of metastatic breast cancer. The clinical relevance of our findings is further supported by our discovery that high-level expression of ABL2 and eight validated downstream targets correlated with decreased disease-free survival in a data set of 971 invasive breast cancer patients (Figure 2). These findings were published in Wang et al. 2016 Science Signaling 9, issue 413: ra12 (cover article of the February 2, 2016 issue).