Zamora Irene, Gutiérrez Mirian, Pascual Alex, Pajares María J, Barajas Miguel, Perez Lillian M, You Sungyong, Knudsen Beatrice S, Freeman Michael R, Encío Ignacio J, Rotinen Mirja
Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
IdiSNA, Navarre Institute for Health Research, Pamplona, Navarre, Spain.
Cell Oncol (Dordr). 2025 Feb;48(1):83-99. doi: 10.1007/s13402-024-00957-3. Epub 2024 May 31.
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 (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC.
We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo.
OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. 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.
The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.
肿瘤异质性使患者治疗复杂化，可能是由于癌细胞跨表型细胞状态转变所致。这一过程与从致癌驱动因素（如乳腺癌（BC）中的雌激素受体（ER））中获得独立性相关，从而导致肿瘤进展、治疗失败和转移扩散。转录因子ONECUT2（OC2）已被证明是转移性去势抵抗性前列腺癌（mCRPC）肿瘤的主要调节蛋白，可促进向耐药神经内分泌（NEPC）表型的谱系可塑性。在此，我们研究OC2在BC不同分子亚型之间动态转换中的作用。
我们使用公共数据库和免疫组织化学染色分析BC中OC2的表达及其临床意义。在体外，OC2强制表达后，我们进行RNA测序、逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹分析。我们还在体外和体内评估了OC2沉默以及用一种类药物小分子抑制的细胞效应。
OC2在相当一部分激素受体阴性的人类BC肿瘤和他莫昔芬耐药模型中高表达，且与不良临床结局、淋巴结转移和更高的临床分期相关。OC2抑制ER表达和活性，抑制与管腔分化相关的基因表达程序，并在基因表达水平激活基底样状态。我们还表明，在转移性BC模型中，细胞生长和存活需要OC2，并且它可以被一种小分子抑制剂靶向，为OC2活性肿瘤患者提供了一种新的治疗策略。
转录因子OC2是BC异质性的驱动因素，也是乳腺肿瘤中不同细胞状态下的潜在药物靶点。
