PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation.
Patients with triple-negative breast cancers (TNBC) are at high risk for recurrent or metastatic disease despite standard treatment, underscoring the need for novel therapeutic targets and strategies. Here we report that protein tyrosine kinase 6 (PTK6) is expressed in approximately 70% of TNBCs where it acts to promote survival and metastatic lung colonization. PTK6 downregulation in mesenchymal TNBC cells suppressed migration and three-dimensional culture growth, and enhanced anoikis, resistance to which is considered a prerequisite for metastasis. PTK6 downregulation restored E-cadherin levels via proteasome-dependent degradation of the E-cadherin repressor SNAIL. Beyond being functionally required in TNBC cells, kinase-active PTK6 also suppressed E-cadherin expression, promoted cell migration, and increased levels of mesenchymal markers in nontransformed MCF10A breast epithelial cells, consistent with a role in promoting an epithelial-mesenchymal transition (EMT). SNAIL downregulation and E-cadherin upregulation mediated by PTK6 inhibition induced anoikis, leading to impaired metastatic lung colonization in vivo Finally, effects of PTK6 downregulation were phenocopied by treatment with a recently developed PTK6 kinase inhibitor, further implicating kinase activity in regulation of EMT and metastases. Our findings illustrate the clinical potential for PTK6 inhibition to improve treatment of patients with high-risk TNBC. Cancer Res; 76(15); 4406-17. ©2016 AACR.
Division of Hematology and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Koichi
K
Ito
Division of Hematology and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Sun Hee
SH
Park
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
Anupma
A
Nayak
Division of Hematology and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Jessica H
JH
Byerly
Division of Hematology and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. hanna.irie@mssm.edu.
Hanna Y
HY
Irie
D002465:Cell Movement; D005260:Female; D006801:Humans; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human