Abstract P3-06-06: Lactate dehydrogenase B in breast cancer contributes to glycolytic phenotype and predicts response to neoadjuvant chemotherapy

Abstract

Abstract Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic heterogeneity is less well understood. This study aimed to identify and evaluate metabolic biomarkers in breast cancers and determine their ability to predict outcomes. Methods: mRNA microarray data from breast cancer cell lines were used to identify bimodal genes, those with the highest potential for robust high/low classification in a clinical setting. Using a panel of breast cancer cell lines, expression and activity of the highest scoring bimodal metabolism gene, lactate dehydrogenase B (LDHB), was quantified and associated with glycolytic phenotype. The contribution of LDHB to glycolysis was evaluated using MDA-MB-231 and HCC1937 cell lines with stable lentiviral knockdown of LDHB. mRNA expression of LDHB was evaluated for association with neoadjuvant chemotherapy response within clinical and PAM50-derived subtypes. Results: LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using four independent patient datasets, LDHB mRNA expression was positively associated with basal subtype and negatively associated with luminal and HER2 subtypes. Furthermore, LDHB predicted basal phenotype independently of hormone-receptor (HR) clinical status (OR = 21.6 for HR-positive/HER2-negative and OR = 18.2 for triple-negative). While LDHB expression could predict basal phenotype, high LDHB expression identified aggressive breast cancer tumors that were primarily but not exclusively basal. Importantly, high LDHB expression predicted pathological complete response to neoadjuvant chemotherapy for both hormone receptor (HR) positive/HER2-negative (OR = 4.0, P = .0002) and triple-negative (OR = 3.0, P = .003) cancers. Consistent with increased response to chemotherapy, LDHB expression in basal cancers within the triple-negative group was associated with the proliferative marker CCNB1 (P < .0001). Conclusion: mRNA expression of LDHB as a single marker predicted glycolytic phenotype in cell lines and response to neoadjuvant chemotherapy in breast cancers independently of HR status. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for breast cancer patients treated with neoadjuvant chemotherapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-06.