Journal
CANCER RESEARCH
Volume 81, Issue 17, Pages 4529-4544Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-2685
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Funding
- Spanish Ministry of Economy and Innovation [SAF2013-44739-R, SAF2016-76504-R, PID2019-111052RB-I00, PID2019-104644RB-I00]
- Spanish Institute of Health Carlos III (FEDER funds) [CIBERONCCB16/12/00295]
- AECC Scientific Foundation [PROYE19036MOR]
- Association International for Cancer Research (AICR) [121057]
- Worldwide Cancer Research [SAF2016-76504-R, 16-0295]
- AICR [SAF2016-76504-R, 12-1057]
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This study identifies the crucial role of E2A factors in breast cancer cell sternness, metastasis, and drug resistance, suggesting the potential therapeutic vulnerability of targeting E2A proteins in breast cancer.
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 sternness 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 Snail transcription. Importantly, high E2A and SNAIL1 expression occurred in aggressive human basal-like breast carcinomas, highlighting the relevance of the E2A-Snail 1 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. Significance: These findings identify key functions of E2A factors in breast cancer cell sternness, metastasis, and drug resistance, supporting a therapeutic vulnerability to targeting E2A proteins in breast cancer.
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