治疗性靶向整合素 αvβ6 在乳腺癌中的作用。
Therapeutic targeting of integrin αvβ6 in breast cancer.
机构信息
Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of Histopathology, Molecular Medical Sciences, Nottingham City Hospital NHS Trust, Nottingham, UK (IOE, ARG); Cancer Sciences Division, Southampton General Hospital, Southampton, UK (GJT, DE, WJT); Department of Surgery (AMT, PQ) and Department of Pathology (LJ), Ninewells Hospital and Medical School, Dundee, UK; Hedley Atkins Breast Pathology Laboratory, Guy's Hospital, London, UK (CG); Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventative Medicine, Queen Mary University of London, London, UK (AB); Biogen Idec, Cambridge, MA (SV, PHW); Oncology iMED, AstraZeneca, Macclesfield, UK (JK, STB).
出版信息
J Natl Cancer Inst. 2014 Jun 28;106(8). doi: 10.1093/jnci/dju169. Print 2014 Aug.
BACKGROUND
Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.
METHODS
Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.
RESULTS
High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.
CONCLUSIONS
Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.
背景
整合素 αvβ6 促进癌细胞的迁移、侵袭和存活；然而，αvβ6 在乳腺癌中的相关性和作用尚未阐明。
方法
通过免疫组织化学（n＞2000）测量乳腺癌中整合素亚基β6（β6）的蛋白表达，并在乳腺癌国际分子分类联盟数据集测量 ITGB6 mRNA 表达。使用 Kaplan-Meier 曲线评估总生存期，并进行生物信息学统计分析（Cox 比例风险模型、Wald 检验和卡方检验）。使用抗体（264RAD）阻断和 siRNA 敲低乳腺癌细胞系中的β6，通过流式细胞术、MTT、Transwell 侵袭、接近连接测定和异种移植（n≥3）分别评估 αvβ6 在人表皮生长因子受体 2（HER2）生物学（表达、增殖、侵袭、体内生长）中的作用。对于两个变量使用学生 t 检验；对于三个以上的变量使用单向方差分析，并用 Bonferroni 多重比较检验。使用线性混合模型分析异种移植的生长，然后进行 Wald 检验和生存分析，使用 Log-Rank 检验。所有统计检验均为双侧检验。
结果
整合素亚基β6 的 mRNA 或蛋白表达高与极差的生存率（HR=1.60，95%CI=1.19 至 2.15，P=0.002）和远处转移增加相关。β6 和 HER2 的共表达与预后更差相关（HR=1.97，95%CI=1.16 至 3.35，P=0.01）。单独使用 264RAD 或曲妥珠单抗治疗 MCF-7/HER2-18 和 BT-474 异种移植的生长速度相似（P＜0.001），但 264RAD 与曲妥珠单抗联合使用可有效阻止肿瘤生长，甚至在曲妥珠单抗耐药的 MCF-7/HER2-18 异种移植中也是如此。
结论
单独使用 264RAD 或与曲妥珠单抗联合靶向 αvβ6 可能为治疗高危和曲妥珠单抗耐药的乳腺癌患者提供一种新的治疗方法。
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