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).

肿瘤异质性（tumor heterogeneity）会给患者的临床治疗带来极大挑战，其成因之一是癌细胞跨不同表型细胞状态的动态转变。这一过程与癌细胞摆脱致癌驱动因子的依赖性密切相关，例如乳腺癌中的雌激素受体(ER)，最终可导致肿瘤进展、治疗失败以及远处转移播散。本研究鉴定出转录因子ONECUT2(OC2)为乳腺癌(BC)的谱系可塑性调控因子，其可抑制雌激素轴信号通路，并推动癌细胞从腔型向基底型的表型转化。OC2在大量激素受体阴性的人类乳腺癌肿瘤亚群中呈高表达，且与不良临床结局、淋巴结转移以及更高的临床分期显著相关。本研究同时证实，在转移性乳腺癌模型中，OC2是细胞增殖与存活所必需的调控因子，且可通过小分子抑制剂对其进行靶向干预，为OC2活性阳性的乳腺癌患者提供全新的治疗策略。实验设计：为探究转录因子OC2在乳腺癌不同分子亚型间的动态转化过程中的作用，本研究对过表达OC2（OC2过表达组vs对照组）后的MCF-7与BT-474细胞系进行了RNA测序(RNA-Seq)。