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Fatty acid oxidation is a metabolic gateway that regulates cellular plasticity and supports metastasis in breast cancer.

During cancer progression, cells would reversibly transit among different cell states that differ in their competence to contribute towards tumor growth, survival, and metastasis. The activation of epithelial-mesenchymal transition (EMT) program in cancer cells has often been attributed to enhanced tumorigenic potential and a gain of therapeutic resistance. We hypothesized that by promoting mesenchymal-epithelial transition (MET), the reverse process of EMT, it could induce a loss of tumorigenic potential and increase susceptibility to standard chemotherapeutics. As EMT is a dynamic and reversible process, epigenetic regulations such as histone modifications and DNA methylation are important in regulating and reprogramming the expression of EMT-responsive genes. Hence, we seek to understand how the epigenetic landscape is altered during transitions between cell states. To understand the molecular link between epigenetic regulations and cell state transitions in cancer cells, a high-throughput library screen on epigenetic modifiers was performed. Epigenetic modifying compounds that can induce MET in basal-like breast cancer cells were uncovered. In vitro and in vivo data demonstrate that compounds targeting the non-BET bromodomains were able to promote MET, induce a loss of stem-like properties, and decrease the tumorigenicity of basal-like breast cancer cells. Using various next-generation sequencing approaches, we also elucidated the mechanisms of how targeting non-BET bromodomains would regulate cell state transitions in breast cancers. While epigenetic therapies are effective in the treatment of hematological malignancies, its application in solid tumors is still limited. Here, we propose the possible use of an epigenetic MET inducer for differentiation therapy of the aggressive basal-like breast cancers. Citation Format: Li Ping Toh, Ser Yue Loo, Wai Leong Tam. Epigenetic regulation of cell state transitions and the therapeutic implications in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3833.