alphaBeta-crystallin: A Novel Biomarker in Breast Cancer

αβ-晶状体蛋白：乳腺癌的新型生物标志物

• 批准号: 7187693
• 负责人: VINCENT L. CRYNS
• 金额: $ 18.12万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-12 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7187693
• 关键词: Accounting; Adjuvant; Adjuvant Chemotherapy; Aggressive behavior; Apoptosis; Axillary lymph node group; Biological Markers; Breast; Breast Cancer Cell; Breast Carcinoma; Cancer Patient; Cancer Prognosis; Caspase; Characteristics; Clinical; Clinical Data; Clinical Trials; Collaborations; Crystallins; Cytokeratin; Disease-Free Survival; Doxorubicin; ERBB2 gene; Enrollment; Epithelial Cells; Estrogen Receptor 2; Estrogen Receptor Status; Estrogen receptor negative; Gene Expression; Genes; Heat shock proteins; Hospitals; Immunohistochemistry; Individual; Journals; Lead; Link; Malignant Neoplasms; Mammary Neoplasms; Modeling; Molecular; Multivariate Analysis; National Surgical Adjuvant Breast and Bowel Project; Nature; Neoadjuvant Therapy; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Outcome; Paclitaxel; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Population; Positive Lymph Node; Prognostic Factor; Prognostic Marker; Protein Overexpression; Proteins; Proto-Oncogene Protein c-kit; Publishing; Randomized; Research Personnel; Resistance; Resources; Sampling; Taxane Compound; Testing; Tissue Microarray; Tissues; Treatment Protocols; Universities; Woman; base; cancer diagnosis; caspase-3; chemotherapy; cohort; cyclophosphamide/doxorubicin protocol; indexing; lymph nodes; malignant breast neoplasm; mortality; novel; outcome forecast; prognostic; prospective; response; size; tau Proteins; taxane; tumor

DESCRIPTION (provided by applicant): Breast cancer is the most frequently diagnosed cancer in women worldwide and is a major cause of mortality in women. Although clinical indices, such as tumor size, grade and axillary lymph node metastases, are useful prognostic factors in breast cancer, there is an urgent need to identify tumor biomarkers that more accurately predict clinical outcome and guide specific therapies for individual patients. We have recently demonstrated that the small heat shock protein alphaB-crystallin is a novel oncogenic protein that predicts poor survival in breast cancer patients independent of tumor grade, lymph node status, estrogen receptor and HER-2 status. We also showed that alphaB-crystallin is commonly expressed in basal-like breast tumors, a newly described subset of clinically aggressive, estrogen receptor-negative and ErbB2/HER-2- negative tumors whose pathogenesis is poorly understood. In addition, we have demonstrated that alphaB-crystallin overexpression protects breast cancer cells from apoptosis induced by several chemotherapy agents, but not taxanes. Hence, we hypothesize that alphaB-crystallin is a novel biomarker in breast cancer that independently predicts (1) poor survival and (2) resistance to many chemotherapy drugs but not taxanes. This hypothesis will be tested in well annotated tissue microarrays (TMAs) from (1) ~2000 women enrolled in the NCI-supported NSABP B-28 cooperative clinical trial, which examined the benefit of adding adjuvant (post-surgery) taxol to doxorubicin and cyclosphosphamide in lymph node-positive patients (aim 1); and (2) ~140 patients who received neoadjuvant (pre-surgery) chemotherapy at Northwestern University (aim 2). The aims are: (1) To examine the clinical value of alphaB-crystallin as a prognostic marker and predictor of adjuvant chemotherapy response in breast cancer patients; and (2) To examine the clinical value of alphaB-crystallin as a prognostic marker and predictor of neoadjuvant chemotherapy response in breast cancer patients. In both aims, the expression of alphaB-crystallin will be determined by immunohistochemistry and its association with other tumor characteristics, survival and chemotherapy response will be determined in univariate and multivariate analyses. Relevance: These studies will examine the value of alphaB-crystallin to determine prognosis and predict chemotherapy response in breast cancer patients. In this way, these studies may help guide patient-specific chemotherapy treatment.

描述（由申请人提供）：乳腺癌是全世界女性中最常诊断出的癌症，也是女性死亡的主要原因。尽管肿瘤大小、分级和腋窝淋巴结转移等临床指标是乳腺癌有用的预后因素，但迫切需要确定肿瘤生物标志物，以更准确地预测临床结果并指导个体患者的具体治疗。我们最近证明，小热休克蛋白 αB-晶状体蛋白是一种新型致癌蛋白，它可以预测乳腺癌患者的不良生存率，而与肿瘤分级、淋巴结状态、雌激素受体和 HER-2 状态无关。我们还表明，αB-晶状体蛋白通常在基底样乳腺肿瘤中表达，这是一种新描述的临床侵袭性、雌激素受体阴性和 ErbB2/HER-2 阴性肿瘤的子集，其发病机制尚不清楚。此外，我们还证明，αB-晶状体蛋白过度表达可以保护乳腺癌细胞免受几种化疗药物（但不是紫杉烷）诱导的细胞凋亡。因此，我们假设 αB-晶状体蛋白是乳腺癌中的一种新型生物标志物，可独立预测 (1) 生存率低和 (2) 对许多化疗药物（但不是紫杉烷类）的耐药性。这一假设将在注释良好的组织微阵列 (TMA) 中进行测试，这些组织微阵列来自 (1) 约 2000 名参加 NCI 支持的 NSABP B-28 合作临床试验的女性，该试验检查了在阿霉素中添加辅助（术后）紫杉醇的益处，以及淋巴结阳性患者使用环磷酰胺（目标 1）； (2) ~140 名患者在西北大学接受了新辅助（手术前）化疗（目标 2）。目的是：（1）探讨αB-晶状体蛋白作为乳腺癌患者预后标志物和辅助化疗反应预测因子的临床价值； (2) 探讨αB-晶状体蛋白作为乳腺癌患者新辅助化疗反应的预后标志物和预测因子的临床价值。在这两个目标中，αB-晶状体蛋白的表达将通过免疫组织化学测定，并且其与其他肿瘤特征、生存和化疗反应的关联将在单变量和多变量分析中确定。相关性：这些研究将检验 αB-晶状体蛋白在确定乳腺癌患者预后和预测化疗反应方面的价值。这样，这些研究可能有助于指导患者特异性化疗治疗。