title: A gene transcription signature of obesity in breast cancer.
abstract: 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 ≥ 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.
authors.affiliation: Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Yvonne H
authors.initials: YH
authors.lastname: Sada
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.forename: Helen
authors.initials: H
authors.lastname: Wong
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Dave
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Landis
authors.forename: Harry D
authors.initials: HD
authors.lastname: Bear
authors.forename: Angel
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D053208:Kaplan-Meier Estimate; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011960:Receptors, Estrogen / Q000378:metabolism; D012016:Reference Values; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D007334:Insulin-Like Growth Factor I