alphaBeta-crystallin: A Novel Biomarker in Breast Cancer

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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.