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

Overview & Synopsis

Cancer stem cells (CSC) are considered responsible for tumorinitiation, therapeutic resistance, and metastasis. A comprehen-sive knowledge of the mechanisms governing the acquisition andmaintenance of cancer stemness is crucial for the development ofnew therapeutic approaches in oncology. E2A basic helix–loop–helix (bHLH) transcription factors are associated with epithelial–mesenchymal transition (EMT) and tumor progression, butknowledge of their functional contributions to cancer biologyis still limited. Using a combination ofin vivoandin vitroanalyses in a novel PyMT-E2A conditional knockout mousemodel and derived primary tumor cell lines, we report here anessential role of E2A in stemness, metastasis, and therapeuticresistance in breast cancer. Targeted deletion of E2A in themammary gland impaired tumor-initiating ability and dediffer-entiation potential and severely compromised metastatic com-petence of PyMT-driven mammary tumors. Mechanistic studiesin PyMT-derived cell lines indicated that E2A actions are medi-ated by the upregulation of Snai1 transcription. Importantly,high E2A and SNAIL1 expression occurred in aggressive humanbasal-like breast carcinomas, highlighting the relevance of theE2A–Snail1 axis in metastatic breast cancer. In addition, E2Afactors contributed to the maintenance of genomic integrityand resistance to PARP inhibitors in PyMT and human triple-negative breast cancer cells. Collectively, these results support thepotential for E2A transcription factors as novel targets worthy oftranslational consideration in breast cancer