Petrossian Karineh, Kanaya Noriko, Lo Chiao, Hsu Pei-Yin, Nguyen Duc, Yang Lixin, Yang Lu, Warden Charles, Wu Xiwei, Pillai Raju, Bernal Lauren, Huang Chiun-Sheng, Kruper Laura, Yuan Yuan, Somlo George, Mortimer Joanne, Chen Shiuan
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA, United States.
Department of Breast Health, National Taiwan University Hospital, Taipei City, Taiwan.
Oncotarget. 2018 Jun 12;9(45):27736-27751. doi: 10.18632/oncotarget.25552.
While ER has multiple biological effects, ER-cyclin D1-CDK4/6-RB is a critical pathway for the action of estrogen on the cell cycle, especially for breast cancers that rely on estrogen for growth. The latest and most efficient CDK4/6 inhibitors target the phosphorylation of retinoblastoma (RB) tumor suppressor gene; thus, altering levels of many cell cycle molecules. Estrogen receptor (ER)+/HER2- breast cancers have shown great progression free survival when CDK4/6 inhibitors are combined with endocrine therapies. Here we report the mechanism of antiestrogen (fulvestrant) combination with CDK4/6 inhibitors is due to synergism in the suppression of ER-mediated cell cycle progression. Furthermore, we performed single cell analysis of cells from an estrogen dependent/hormone receptor-positive patient derived xenograft (PDX) tumor model treated with palbociclib. These single cells expressed various levels of ER and RB which are involved in cell cycle regulation; and the response to palbociclib treatment relies not only on the ER-cyclin D1-CDK4/6-RB pathway but it is also dependent on elevated levels of ER and/or RB. Our preclinical studies show that palbociclib response is dependent on cells with ER, which is directly involved in cell cycle progression in hormone receptor positive (HR+) breast cancer.
虽然雌激素受体（ER）具有多种生物学效应，但ER-细胞周期蛋白D1-CDK4/6-RB是雌激素作用于细胞周期的关键途径，尤其是对于依赖雌激素生长的乳腺癌。最新且最有效的CDK4/6抑制剂靶向视网膜母细胞瘤（RB）肿瘤抑制基因的磷酸化；因此，改变了许多细胞周期分子的水平。当CDK4/6抑制剂与内分泌疗法联合使用时，雌激素受体（ER）阳性/人表皮生长因子受体2（HER2）阴性乳腺癌的无进展生存期有了显著延长。在此我们报告，抗雌激素（氟维司群）与CDK4/6抑制剂联合使用的机制是由于在抑制ER介导的细胞周期进程中存在协同作用。此外，我们对来自一名雌激素依赖/激素受体阳性患者来源的异种移植（PDX）肿瘤模型且经哌柏西利治疗的细胞进行了单细胞分析。这些单细胞表达了参与细胞周期调控的不同水平的ER和RB；并且对哌柏西利治疗的反应不仅依赖于ER-细胞周期蛋白D1-CDK4/6-RB途径，还取决于ER和/或RB水平的升高。我们的临床前研究表明，哌柏西利的反应依赖于具有ER的细胞，而ER直接参与激素受体阳性（HR+）乳腺癌的细胞周期进程。
