Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers.

Song W, Hwang Y, Youngblood VM, Cook RS, Balko JM, Chen J, Brantley-Sieders DM
Oncogene. 2017 36 (40): 5620-5630

PMID: 28581527 · PMCID: PMC5629103 · DOI:10.1038/onc.2017.170

Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC.

MeSH Terms (20)

Animals Benzamides Cell Cycle Cell Line, Tumor Cell Proliferation Cyclin-Dependent Kinase Inhibitor p27 Ephrin-A2 Female Gene Knockdown Techniques Humans Mice Mice, Inbred NOD Mice, Nude Mice, SCID Neoplasm Recurrence, Local Niacinamide Protein Kinase Inhibitors Proto-Oncogene Proteins c-myb Triple Negative Breast Neoplasms Xenograft Model Antitumor Assays

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