A gene transcription signature of obesity in breast cancer
A gene transcription signature of obesity in breast cancer
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DOI：
10.1007/s10549-011-1595-y
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发表时间：
2012-04-01
影响因子：
3.8
通讯作者：
Chang, Jenny C.
中科院分区：
文献类型：
--
作者：
Creighton, Chad J.;Sada, Yvonne H.;Chang, Jenny C.
肥胖被认为是导致乳腺癌疾病结局恶化的原因，因为脂肪细胞分泌的内分泌因子、胰岛素和胰岛素样生长因子（IGF）水平升高，加速肿瘤细胞增殖并损害治疗反应。我们通过对一组103个肿瘤的转录谱分析，研究了患者肥胖对原发性乳腺肿瘤基因表达的影响，其中确定了患者的体重指数（BMI）。根据患者的肥胖表型（定义为正常（BMI < 25）、超重（BMI 25-29.9）或肥胖（BMI a千分之30））对样本进行分层。与其他肿瘤相比，肥胖患者乳腺肿瘤中广泛的基因表达改变是明显的，这使我们能够定义662个基因的肥胖相关癌症转录特征。在乳腺癌的多个公开表达数据集（代表> 1，500名患者）中，肥胖特征模式的表现与IGF信号传导的基因特征的表现相关，并且（在较小程度上）与雌激素受体的较低水平相关。在一个患者队列中，肥胖特征的表现与较短的转移时间相关。一些小分子在体外诱导或抑制肥胖相关的转录程序;雌激素α-雌二醇、左炔诺孕酮和己烷雌酚诱导了该程序，而几种靶向神经递质受体通路的抗帕金森病药物抑制了该程序。乳腺癌患者的肥胖似乎会影响肿瘤的基因表达模式（可能是身体化学改变的结果）。这些结果证明了进一步研究肥胖相关的乳腺癌风险和疾病结果的修饰符。
Obesity is thought to contribute to worse disease outcome in breast cancer as a result of increased levels of adipocyte-secreted endocrine factors, insulin, and insulin-like growth factors (IGFs) that accelerate tumor cell proliferation and impair treatment response. We examined the effects of patient obesity on primary breast tumor gene expression, by profiling transcription of a set of 103 tumors for which the patients' body mass index (BMI) was ascertained. Sample profiles were stratified according to patients' obesity phenotype defined as normal (BMI < 25), overweight (BMI 25-29.9), or obese (BMI a parts per thousand yen 30). Widespread gene expression alterations were evident in breast tumors from obese patients as compared to other tumors, allowing us to define an obesity-associated cancer transcriptional signature of 662 genes. In multiple public expression data sets of breast cancers (representing > 1,500 patients), manifestation of the obesity signature patterns correlated with manifestation of a gene signature for IGF signaling and (to a lesser extent) with lower levels of estrogen receptor. In one patient cohort, manifestation of the obesity signature correlated with shorter time to metastases. A number of small molecules either induced or suppressed the obesity-associated transcriptional program in vitro; estrogens alpha-estradiol, levonorgestrel, and hexestrol induced the program, while several anti-parkinsonian agents targeting neurotransmitter receptor pathways repressed the program. Obesity in breast cancer patients appears to impact the gene expression patterns of the tumor (perhaps as a result of altered body chemistry). These results warrant further investigation of obesity-associated modifiers of breast cancer risk and disease outcome.