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首页> 外文期刊>Molecular cancer therapeutics >Chemogenetic Evaluation of the Mitotic Kinesin CENP-E Reveals a Critical Role in Triple-Negative Breast Cancer
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Chemogenetic Evaluation of the Mitotic Kinesin CENP-E Reveals a Critical Role in Triple-Negative Breast Cancer

机译：有丝分裂驱动蛋白CENP-E的化学遗传学评价显示三阴性乳腺癌中的关键作用。

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Breast cancer patients with tumors lacking the three diagnostic markers (ER, PR, and HER2) are classified as triple-negative (primarily basal-like) and have poor prognosis because there is no disease-specific therapy available. To address this unmet medical need, gene expression analyses using more than a thousand breast cancer samples were conducted, which identified elevated centromere protein E (CENP-E) expression in the basal-a molecular subtype relative to other subtypes. CENP-E, a mitotic kinesin component of the spindle assembly checkpoint, is shown to be induced in basal-a tumor cell lines by the mitotic spindle inhibitor drug docetaxel. CENP-E knockdown by inducible shRNA reduces basal-a breast cancer cell viability. A potent, selective CENP-E inhibitor (PF-2771) was used to define the contribution of CENP-E motor function to basal-like breast cancer. Mechanistic evaluation of PF-2771 in basal-a tumor cells links CENP-E-dependent molecular events (e.g., phosphorylation of histone H3 Ser-10; phospho-HH3-Ser(10)) to functional outcomes (e.g., chromosomal congression defects). Across a diverse panel of breast cell lines, CENP-E inhibition by PF-2771 selectively inhibits proliferation of basal breast cancer cell lines relative to premalignant ones and its response correlates with the degree of chromosomal instability. Pharmacokinetic-pharmacodynamic efficacy analysis in a basal-a xenograft tumor model shows that PF-2771 exposure is well correlated with increased phospho-HH3-Ser(10) levels and tumor growth regression. Complete tumor regression is observed in a patient-derived, basal-a breast cancer xenograft tumor model treated with PF-2771. Tumor regression is also observed with PF-2771 in a taxane-resistant basal-a model. Taken together, CENP-E may be an effective therapeutic target for patients with triple-negative/basal-a breast cancer. (C) 2014 AACR.
机译：缺乏三种诊断标记（ER，PR和HER2）的乳腺癌患者被分类为三阴性（主要是基底样），并且由于没有可用的疾病特异性疗法而预后较差。为了满足这种未满足的医学需求，进行了使用一千多个乳腺癌样品的基因表达分析，该分析确定了相对于其他亚型的基底-a分子亚型中着丝粒蛋白E（CENP-E）表达升高。 CENP-E，纺锤体装配检查点的有丝分裂驱动蛋白成分，已显示是由有丝分裂纺锤体抑制剂多西他赛在基底-a肿瘤细胞系中诱导产生的。诱导型shRNA的CENP-E敲低降低了基础a乳腺癌细胞的生存能力。一种有效的选择性CENP-E抑制剂（PF-2771）用于定义CENP-E运动功能对基底样乳腺癌的贡献。基底细胞肿瘤细胞中PF-2771的机理评估将CENP-E依赖性分子事件（例如组蛋白H3 Ser-10的磷酸化;磷酸化HH3-Ser（10））与功能结果（例如染色体国会缺陷）联系起来。 。在各种乳腺癌细胞系中，相对于癌前细胞，PF-2771对CENP-E的抑制作用选择性抑制了基础乳腺癌细胞系的增殖，并且其反应与染色体不稳定性程度相关。在基础-a异种移植肿瘤模型中的药代动力学药效学分析表明，PF-2771暴露与磷酸化HH3-Ser（10）水平增加和肿瘤生长消退密切相关。在用PF-2771治疗的患者来源的基底-乳腺癌异种移植肿瘤模型中观察到肿瘤完全消退。在抗紫杉烷的基础-a模型中，PF-2771也观察到肿瘤消退。综上所述，CENP-E可能是三阴性/基底性乳腺癌患者的有效治疗靶标。 （C）2014 AACR。

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