alphaBeta-crystallin: A Novel Biomarker in Breast Cancer

描述（由申请人提供）：乳腺癌是全世界女性最常诊断的癌症，也是女性死亡的主要原因。虽然临床指标，如肿瘤大小，分级和腋窝淋巴结转移，是有用的预后因素在乳腺癌，有迫切需要确定肿瘤生物标志物，更准确地预测临床结果和指导具体的治疗方案，为个别患者。我们最近证明，小热休克蛋白α B-晶体蛋白是一种新的致癌蛋白，预测乳腺癌患者的生存率不高，与肿瘤分级、淋巴结状态、雌激素受体和HER-2状态无关。我们还发现α B-晶状体蛋白通常在基底样乳腺肿瘤中表达，基底样乳腺肿瘤是一种新描述的临床侵袭性、雌激素受体阴性和ErbB 2/HER-2阴性肿瘤的子集，其发病机制知之甚少。此外，我们已经证明，α B-晶状体蛋白过表达保护乳腺癌细胞免于由几种化疗药物诱导的凋亡，但不是紫杉烷。因此，我们假设α B-晶状体蛋白是乳腺癌中的一种新的生物标志物，其独立地预测（1）较差的存活率和（2）对许多化疗药物的耐药性，但不是紫杉烷类。这一假设将在来自参加NCI支持的NSABP B-28合作临床试验的约2000名妇女的注释良好的组织微阵列（TMA）中进行测试，该试验检查了添加佐剂的益处。淋巴结阳性患者中（术后）紫杉醇与阿霉素和环磷酰胺的比较（目的1）;（2）在西北大学接受新辅助（术前）化疗的~140例患者（目的2）。其目标是：（1）检查α B-晶体蛋白作为乳腺癌患者辅助化疗反应的预后标志物和预测因子的临床价值;和（2）检查α B-晶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，将通过免疫组织化学确定α B-晶状体蛋白的表达，并将在单变量和多变量分析中确定其与其他肿瘤特征、生存期和化疗反应的相关性。相关性：这些研究将检查alphaB-晶状体蛋白的价值，以确定预后和预测乳腺癌患者的化疗反应。通过这种方式，这些研究可能有助于指导患者特异性化疗治疗。

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.