RESUMO
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.
Assuntos
Ciclo Celular , Efrina-A2/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Benzamidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Efrina-A2/antagonistas & inibidores , Efrina-A2/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Recidiva Local de Neoplasia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-myb/metabolismo , Receptor EphA2 , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The TAL1/SCL transcription factor is essential for haematopoietic commitment and vascular remodelling during embryonic development. To help clarify its role in postnatal vascular processes, we characterized the expression of mouse Tal1 protein by immunocytochemistry in several experimental models of blood vessel formation. In adult mice, Tal1 protein was expressed in rare microvascular endothelial cells and in extravascular cells provisionally identified as endothelial progenitors from their morphology, proximity to vessels and expression of vascular endothelial growth factor receptor-2. The number of Tal1-expressing endothelial cells increased significantly but transiently in all the models-hormone-induced ovulation, wound healing and tumour development. Finally, Tal1 protein was detected in the nuclei of newly formed lymphatic endothelial cells in tumour-bearing animals. These results show that TAL1 is expressed by vascular endothelial cells and endothelial progenitors at sites of physiological and pathological neovascularization and suggest a role for this transcription factor in adult vasculogenesis. This work also provides the first evidence for TAL1 expression in lymphangiogenesis.
