E2A Modulates Stemness, Metastasis, and Therapeutic Resistance of Breast Cancer

© 2021 The Authors.
Cancer stem cells (CSC) are considered responsible for tumor initiation, therapeutic resistance, and metastasis. A comprehensive knowledge of the mechanisms governing the acquisition and maintenance of cancer stemness is crucial for the development of new therapeutic approaches in oncology. E2A basic helix–loop–helix (bHLH) transcription factors are associated with epithelial–mesenchymal transition (EMT) and tumor progression, but knowledge of their functional contributions to cancer biology is still limited. Using a combination of in vivo and in vitro analyses in a novel PyMT-E2A conditional knockout mouse model and derived primary tumor cell lines, we report here an essential role of E2A in stemness, metastasis, and therapeutic resistance in breast cancer. Targeted deletion of E2A in the mammary gland impaired tumor-initiating ability and dedifferentiation potential and severely compromised metastatic competence of PyMT-driven mammary tumors. Mechanistic studies in PyMT-derived cell lines indicated that E2A actions are mediated by the upregulation of Snai1 transcription. Importantly, high E2A and SNAIL1 expression occurred in aggressive human basal-like breast carcinomas, highlighting the relevance of the E2A–Snail1 axis in metastatic breast cancer. In addition, E2A factors contributed to the maintenance of genomic integrity and resistance to PARP inhibitors in PyMT and human triple-negative breast cancer cells. Collectively, these results support the potential for E2A transcription factors as novel targets worthy of translational consideration in breast cancer.
This work has been supported by grants from the Spanish Ministry of Economy and Innovation (SAF2013–44739-R, SAF2016–76504-R to A. Cano and F. Portillo), PID2019–111052RB-I00 to F. Portillo, PID2019–104644RB-I00 to G. Moreno-Bueno; the Spanish Institute of Health Carlos III (CIBERONC-CB16/12/00295 to A. Cano, G. Moreno-Bueno; all of them partly supported by FEDER funds); the AECC Scientific Foundation 2019 (PROYE19036MOR to G. Moreno-Bueno); the Association International for Cancer Research (AICR; 12–1057 to A. Cano, P.G. Santamaría); and Worldwide Cancer Research (16–0295 to A. Cano, F. Portillo, and P.G. Santamaría). A. Vázquez-Naharro was funded by a PhD contract from SAF2016–76504-R grant; V. Santos by AICR (12–1057) and SAF2016–76504-R grants; P.G. Santamaría by a research contract of the AECC Scientific Foundation, and from Worldwide Cancer Research (16–0295) and SAF2016–76504-R grants.