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.
Fig. 1 – (A) Bioluminescent images of bone metastasis from representative mice at day 35 after inoculation with control (Scr) or ABL1/ABL2 knockdown (shAA) breast cancer cells. (B) Quantification of bone metastasis. (C) Representative 3D micro-CT reconstruction of mouse bones after injection of control and ABL1/ABL2 knockdown (shAA) breast cancer cells breast cancer cells. (D) Quantification of bone density. Image courtesy of Jun Wang.
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).
Fig. 2 – (A) Kaplan-Meier representation of the probability of cumulative overall disease-free survival in TCGA dataset with 971 invasive breast cancer patients according to whether the ABL signature (ABL2, TAZ, AXL, CTGF, STAT5A, STAT5B, TNC, IL6, and MMP1) was altered or not. (B) Model for the role of ABL kinases in the regulation of breast cancer bone metastasis. Image courtesy of Jun Wang.
