新辅助化疗是目前影响乳腺癌手术成功率的关键因素。另外，新辅助化疗也能够影响肿瘤细胞对化疗的敏感性。一般情况下，仅有少部分乳腺癌患者对于新辅助化疗有反应，不幸的是，目前没有精确预测反应患者群体的有效方法，另外，目前急需解决过度的化疗给患者带来的严重不良反应。一些研究试图寻找能够预测新辅助化疗反应性的生物标记，从而降低化疗带来的的副作用以及致死风险，这对于乳腺癌的治疗具有重要的意义。
微核糖核酸（miRNA）是一类高度保守的短链非编码RNA，能够负向调节基因表达。既往研究已经发现：大量miRNA在乳腺癌细胞中存在表达升高或下降，这进一步影响了癌细胞的发生以及耐药性。miRNA-205是一类肿瘤抑制因子，乳腺癌中过表达miRNA-205能够有效抑制细胞的复制并促进其凋亡。
2016年6月30日，英国《自然》旗下《细胞死亡与疾病》在线发表中国天津乳腺癌防治研究中心、天津医科大学肿瘤医院、国家肿瘤临床医学研究中心、乳腺癌防治教育部重点实验室、英国伦敦帝国学院哈默史密斯医院的研究报告，深入探讨了miRNA-205对于乳腺癌发生的意义以及能否作为预测乳腺癌对化疗敏感性的生物标志物。
该研究比较了对新辅助化疗效果各异的乳腺癌患者体内癌细胞miRNA-205表达水平。结果发现，miRNA-205表达量与癌细胞对新辅助化疗敏感度之间存在显著相关性，这意味着miRNA-205的表达量越高，患者对化疗的敏感程度也就越高。
于是，该研究人为地了提高了耐药性乳腺癌细胞MCF-7/A02与CALDOX的miRNA-205表达量，发现这能够使这些细胞对化疗药物的敏感度增加。该研究进一步发现miRNA-205过表达能够促进细胞凋亡，尤其是提高胱天蛋白酶的活性以及调节其他与细胞凋亡信号通路相关蛋白质的活性。此外，miRNA-205还能负向调节VEGFA与FGF2的表达量，这一作用对于提高乳腺癌细胞的敏感性具有关键作用。
然后，该研究在癌细胞中加入VEGFA/FGF2，再进行药物刺激，结果发现能够大幅提高乳腺癌细胞对化疗药物的耐药性。
最后，该研究通过小鼠试验证实miRNA-205对提高乳腺癌细胞对化疗药物敏感性的作用。
Cell Death Dis. 2016 Jun 30;7(6):e2291.
miRNA-205 targets VEGFA and FGF2 and regulates resistance to chemotherapeutics in breast cancer.
Hu Y, Qiu Y, Yagüe E, Ji W, Liu J, Zhang J.
China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, PR China; Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Tianjin 300060, PR China; Cancer Research Center, Division of Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
MicroRNAs (miRNAs) have critical roles in regulating cancer cell survival, proliferation and sensitivity to chemotherapy. The potential application of using miRNAs to predict chemotherapeutic response to cancer treatment is highly promising. However, the underlying mechanisms of chemotherapy response control by miRNAs remain to be fully identified and their prognostic value has not been fully evaluated. Here we show a strong correlation between miR-205 expression and chemosensitivtiy to TAC (docetaxol, doxorubicin plus cyclophosphamide), a widely-used neoadjuvant chemotherapy (NAC) regimen, for breast cancer patients. High level of miR-205 predicted better response to TAC regimen NAC in breast cancer patients. We found miR-205 downregulated in both MCF-7/A02 and CALDOX cells, two drug-resistant derivatives of MCF-7 and Cal51 cells, and its ectopic expression led to an increase in apoptosis resensitization of both drug-resistant cell lines to doxorubicin and taxol. We further show that miR-205 directly binds VEGFA and FGF2 mRNA 3'-UTRs and confirm that miR-205 levels are negatively correlated with VEGFA and FGF2 mRNA expression in breast cancer patients. Adding VEGFA and FGF2 exogenously to chemosensitive breast cancer cells and chemoresistant cells with miR-205 overexpression led to drug resistance. Consistently, low VEGFA and FGF2 expression correlated with better response to NAC in breast cancer patients. In addition, inhibition of tumor growth and resensitization to doxorubicin were also observed in mouse tumor xenografts from cells overexpressing miR-205. Taken together, our data suggest that miR-205 enhances chemosensitivity of breast cancer cells to TAC chemotherapy by suppressing both VEGFA and FGF2, leading to evasion of apoptosis. MiR-205 may serve as a predictive biomarker and a potential therapeutic target in breast cancer treatment.
PMID: 27362808
DOI: 10.1038/cddis.2016.194
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