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Abstract
Metastatic dissemination of cancer cells from the primary tumor and their spread to distant sites in the body is the leading cause of mortality in breast cancer patients. While researchers have identified treatments that shrink or slow metastatic tumors, no treatment that permanently eradicates metastasis exists at present. Here, we show that the ABL kinase inhibitors imatinib, nilotinib, and GNF-5 impede invadopodium precursor formation and cortactin-phosphorylation dependent invadopodium maturation, leading to decreased actin polymerization in invadopodia, reduced extracellular matrix degradation, and impaired matrix proteolysis-dependent invasion. Using a mouse xenograft model we demonstrate that, while primary tumor size is not affected by ABL kinase inhibitors, the in vivo matrix metalloproteinase (MMP) activity, tumor cell invasion, and consequent spontaneous metastasis to lungs are significantly impaired in inhibitor-treated mice. Further proteogenomic analysis of breast cancer patient databases revealed co-expression of the Abl-related gene (Arg) and cortactin across all hormone- and human epidermal growth factor receptor 2 (HER2)-receptor status tumors, which correlates synergistically with distant metastasis and poor patient prognosis. Our findings establish a prognostic value for Arg and cortactin as predictors of metastatic dissemination and suggest that therapeutic inhibition of ABL kinases may be used for blocking breast cancer metastasis.
Highlights
While primary tumors can often be surgically removed and are usually responsible for only a small percentage of cancer deaths, complications associated with distant metastasis are the primary cause of mortality from cancer and serve as an important target for potential therapeutic intervention
Using a mouse xenograft model we demonstrate that, while primary tumor size is not affected by ABL kinase inhibitors, the in vivo matrix metalloproteinase (MMP) activity, tumor cell invasion, and consequent spontaneous metastasis to lungs are significantly impaired in inhibitor-treated mice
Treatment with ABL kinase inhibitors significantly reduced cortactin tyrosine phosphorylation in invadopodia and consequent actin polymerization, matrix degradation, and 3D tumor cell invasion. These effects were correlated with the ability of ABL kinase inhibitors to significantly decrease the in vivo MMP-mediated matrix degradation and invasiveness of cancer cells within the primary tumor, and with decreased pulmonary metastasis of breast cancer cells in a xenograft mouse model
Summary
While primary tumors can often be surgically removed and are usually responsible for only a small percentage of cancer deaths, complications associated with distant metastasis are the primary cause of mortality from cancer and serve as an important target for potential therapeutic intervention. Similar chromosomal translocation of the TEL transcription factor gene next to Arg have been detected in rare cases of acute myeloid leukemias [18,19,20,21]. These fusion genes encode constitutively activated forms of Abl and Arg kinases that are required for cellular transformation. Activation of ABL kinases in solid tumors is not linked to chromosomal translocation events, but is rather characterized by their enhanced expression and activation due to amplification, increased gene or protein expression, or increased activity in response to stimulation by oncogenic tyrosine kinase and chemokine receptors, oxidative stress, and metabolic stress [13]
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