A gene transcription signature of obesity in breast cancer

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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.

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Abbreviations

BMI:

Body mass index

ER:

Estrogen receptor (alpha)

IGF:

Insulin-like growth factor

CMap:

Connectivity map

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Acknowledgments

The authors deeply thank Drs. Peter O’Connell and Diane Wilson for their preliminary guidance in the formulation of this research study. This study was supported in part by the National Institutes of Health Grant P30CA125123, the National Cancer Institute Breast Cancer SPORE Grant P50 CA50183, National Cancer Institute Grant 5R01CA138197-02, and the US Army Medical Research and Material Command DAMD17-01-0132 and W81XWH-04-1-0468.

Conflicts of interest

None.

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Correspondence to Jenny C. Chang.

Additional information

Chad J. Creighton and Yvonne H. Sada contributed equally to this study

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Creighton, C.J., Sada, Y.H., Zhang, Y. et al. A gene transcription signature of obesity in breast cancer. Breast Cancer Res Treat 132, 993–1000 (2012). https://doi.org/10.1007/s10549-011-1595-y

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Keywords

  • Obesity
  • Breast cancer
  • BMI
  • Insulin-like growth factor
  • IGF
  • Gene expression profiling