Kimbung Siker, Lettiero Barbara, Feldt Maria, Bosch Ana, Borgquist Signe
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
Department of Oncology, Skåne University Hospital, Lund, Sweden.
Oncotarget. 2016 Sep 13;7(37):59640-59651. doi: 10.18632/oncotarget.10746.
There is sufficient evidence that statins have a protective role against breast cancer proliferation and recurrence, but treatment predictive biomarkers are lacking. Breast cancer cell lines displaying diverse sensitivity to atorvastatin were subjected to global transcriptional profiling and genes significantly altered by statin treatment were identified. Atorvastatin treatment strongly inhibited proliferation in estrogen receptor (ER) negative cell lines and a commensurate response was also evident on the genome-wide transcriptional scale, with ER negative cells displaying a robust deregulation of genes involved in the regulation of cell cycle progression and apoptosis. Interestingly, atorvastatin upregulated genes involved in the cholesterol biosynthesis pathway in all cell lines, irrespective of sensitivity to statin treatment. However, the level of pathway induction; measured as the fold change in transcript levels, was inversely correlated to the effect of statin treatment on cell growth. High expression of cholesterol biosynthesis genes before treatment was associated with resistance to statin therapy in cell lines and clinical biopsies. Furthermore, high expression of cholesterol biosynthesis genes was independently prognostic for a shorter recurrence-free and overall survival, especially among ER positive tumors. Dysregulation of cholesterol biosynthesis is therefore predictive for both sensitivity to anti-cancer statin therapy and prognosis following primary breast cancer diagnosis.
有充分证据表明他汀类药物对乳腺癌的增殖和复发具有保护作用，但缺乏治疗预测生物标志物。对显示出对阿托伐他汀具有不同敏感性的乳腺癌细胞系进行了全基因组转录谱分析，并鉴定了因他汀类药物治疗而显著改变的基因。阿托伐他汀治疗强烈抑制雌激素受体（ER）阴性细胞系的增殖，并且在全基因组转录水平上也有相应反应，ER阴性细胞显示出参与细胞周期进程和凋亡调控的基因出现明显失调。有趣的是，无论对他汀类药物治疗的敏感性如何，阿托伐他汀在所有细胞系中均上调了参与胆固醇生物合成途径的基因。然而，以转录水平的倍数变化衡量的途径诱导水平与他汀类药物治疗对细胞生长的影响呈负相关。治疗前胆固醇生物合成基因的高表达与细胞系和临床活检中对他汀类药物治疗的耐药性相关。此外，胆固醇生物合成基因的高表达独立预示着无复发生存期和总生存期较短，尤其是在ER阳性肿瘤中。因此，胆固醇生物合成失调对于抗癌他汀类药物治疗的敏感性和原发性乳腺癌诊断后的预后均具有预测作用。
