Estrogen receptor (ER)-positive breast cancer is characterized by late recurrences following initial treatment. The epithelial cell fate transcription factor Grainyhead-like protein 2 (GRHL2) is overexpressed in ER-positive breast cancers and is linked to poorer prognosis as compared to ER-negative breast cancers. To understand how GRHL2 contributes to progression, GRHL2 was overexpressed in ER-positive cells. We demonstrated that elevated GRHL2 imparts plasticity with stem cell- and dormancy-associated traits. RNA sequencing and immunocytochemistry revealed that high GRHL2 not only strengthens the epithelial identity but supports a hybrid epithelial to mesenchymal transition (EMT). Proliferation and tumor studies exhibited a decrease in growth and an upregulation of dormancy markers, such asNR2F1andCDKN1B. Mammosphere assays and flow cytometry revealed enrichment of stem cell markers CD44 and ALDH1, and increased self-renewal capacity. Cistrome analyses revealed a change in transcription factor motifs near GRHL2 sites from developmental factors to those associated with disease progression. Together, these data support the idea that the plasticity and properties induced by elevated GRHL2 may provide a selective advantage to explain the association between GRHL2 and breast cancer progression.
雌激素受体（ER）阳性乳腺癌的特征在于初始治疗后出现晚期复发。上皮细胞命运转录因子Grainyhead-like蛋白2（GRHL2）在ER阳性乳腺癌中过度表达，与ER阴性乳腺癌相比，其预后较差。为探究GRHL2如何促进疾病进展，我们在ER阳性细胞中过表达了GRHL2。研究发现，GRHL2水平升高可赋予细胞可塑性，使其表现出干细胞特性及休眠相关特征。RNA测序与免疫细胞化学分析显示，高表达的GRHL2不仅增强上皮特性，同时支持上皮-间质转化（EMT）的混合状态。增殖与肿瘤实验表明细胞生长减缓，且休眠标志物如NR2F1和CDKN1B表达上调。乳腺球形成实验与流式细胞术显示干细胞标志物CD44和ALDH1富集，自我更新能力增强。顺式作用元件组分析揭示GRHL2结合位点附近的转录因子基序从发育相关因子转变为与疾病进展相关的因子。综上，这些数据支持以下观点：GRHL2升高诱导的可塑性及相关特性可能提供选择性优势，从而解释GRHL2与乳腺癌进展之间的关联。
Elevated GRHL2 Imparts Plasticity in ER-Positive Breast Cancer Cells
肿瘤(癌症)患者之家