Lactate dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer.
Lactate dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-13-0623
复制
发表时间：
2013-07-01
期刊：
影响因子：
--
通讯作者：
Mills GB
中科院分区：
文献类型：
--
作者：
Dennison JB;Molina JR;Mitra S;González-Angulo AM;Balko JM;Kuba MG;Sanders ME;Pinto JA;Gómez HL;Arteaga CL;Brown RE;Mills GB
虽然乳腺癌是已知的分子异质性，其代谢表型是不太好理解，并可能预测化疗的反应。本研究旨在评估代谢基因作为乳腺癌个体预测生物标志物的价值。使用来自乳腺癌细胞系的mRNA微阵列数据来鉴定双峰基因-在临床测定中具有最大潜力的稳健高/低分类的那些基因。在体外评价了评分最高的代谢基因乳酸脱氢酶B（LDHB）的代谢功能。其表达与临床和PAM 50衍生亚型的新辅助化疗反应和复发相关。LDHB在具有糖酵解、基底样表型的细胞系中高度表达。细胞系中LDHB的稳定敲低降低了糖酵解依赖性，将LDHB表达直接与代谢功能联系起来。使用患者数据集，LDHB在基底细胞样癌症中高度表达，并且可以预测临床组内的基底细胞样亚型（对于受体（HR）阳性/HER 2阴性，比值比= 21;对于三阴性，比值比= 10）。此外，高LDHB预测HR阳性/HER 2阴性（比值比= 4.1，P <0.001）和三阴性（比值比= 3.0，P = 0.003）癌症对新辅助化疗的病理学完全缓解（pCR）。对于无pCR的三阴性肿瘤，治疗后高LDHB也可识别复发风险增加的增殖性肿瘤（风险比= 2.2，P = 0.006）。LDHB表达预测临床亚型对新辅助化疗的反应，与标准预后标志物和PAM 50亚型无关。这些观察结果支持将LDHB作为接受新辅助化疗的乳腺癌患者缓解的预测标志物的前瞻性临床评价。
Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less well understood and may predict response to chemotherapy. This study aimed to evaluate metabolic genes as individual predictive biomarkers in breast cancer. mRNA microarray data from breast cancer cell lines were used to identify bimodal genes – those with highest potential for robust high/low classification in clinical assays. Metabolic function was evaluated in vitro for the highest scoring metabolic gene, lactate dehydrogenase B (LDHB). Its expression was associated with neoadjuvant chemotherapy response and relapse within clinical and PAM50-derived subtypes. LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Stable knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using patient datasets, LDHB was highly expressed in basal-like cancers and could predict basal-like subtype within clinical groups (odds ratio = 21 for hormone-receptor (HR)-positive/HER2-negative; odds ratio = 10 for triple-negative). Furthermore, high LDHB predicted pathological complete response (pCR) to neoadjuvant chemotherapy for both HR-positive/HER2-negative (odds ratio = 4.1, P < .001) and triple-negative (odds ratio = 3.0, P = .003) cancers. For triple-negative tumors without pCR, high LDHB post-treatment also identified proliferative tumors with increased risk of recurrence (hazard ratio = 2.2, P = .006). Expression of LDHB predicted response to neoadjuvant chemotherapy within clinical subtypes independently of standard prognostic markers and PAM50-subtyping. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for breast cancer patients receiving neoadjuvant chemotherapy.