ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity [OE_MCF7]
Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer, resulting in tumor progression, therapeutic failure and metastatic spread. Here we identify the transcription factor ONECUT2 (OC2) as a lineage plasticity regulator of breast cancer (BC) that suppresses the estrogen axis and promotes luminal to basal transition. OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. Overall design: To investigate the role of the transcription factor OC2 in the dynamic conversion between different molecular subtypes in  breast cancer, we performed RNA-Seq in MCF-7 and BT-474 cell lines after enforced expression of OC2 (OC2-OE vs C).