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Not All Fat Is Equal: Differential Gene Expression and Potential Therapeutic Targets in Subcutaneous Adipose, Visceral Adipose, and Endometrium of Obese Women With and Without Endometrial Cancer
  1. Susan C. Modesitt, MD, FACOG, FACS*,
  2. Jennifer Y Hsu, BA,
  3. Sudhir R. Chowbina, MS,
  4. Robert T. Lawrence, BS§ and
  5. Kyle L. Hoehn, PhD§
  1. *Division of Gynecologic Oncology, Obstetrics and Gynecology Department, University of Virginia Health System;
  2. School of Medicine, University of Virginia;
  3. Advanced Biomedical Computing Center, National Cancer Institute-Frederick/SAIC-Frederick Inc, Frederick, MD; and
  4. §Department of Pharmacology, University of Virginia Health System, Charlottesville, VA.
  1. Address correspondence and reprint requests to Susan C. Modesitt, MD, FACOG, FACS, Gynecologic Oncology Division, Obstetrics and Gynecology Department, University of Virginia Health System, Box 800712, Charlottesville, VA 22908-0712. E-mail: scm6h@virginia.edu.

Abstract

Objective To identify obesity-related cancer genes in endometrial and adipose tissue depots of body mass index–matched morbidly obese women with and without endometrial cancer.

Methods Eight women undergoing hysterectomy (4 women with and 4 women without endometrial cancer) were matched by age (52.6 years) and body mass index (44.5 kg/m2). Endometrium, visceral adipose tissue, and subcutaneous adipose tissue were collected and subjected to microarray analysis using Affymetrix Human Genome U133 Plus 2.0 Arrays. Gene set enrichment analysis used to extract biological information from the gene expression data and t test metric ranked and compared genes in the expression data set. Protein expression was measured in the endometrial samples, and serum was collected for hormone/metabolite assays.

Results No significant differences were detected in hormone/metabolite levels between groups. Gene set enrichment analysis comparisons demonstrated that endometrial, visceral adipose and subcutaneous adipose tissues displayed 40, 47, and 38 alternatively regulated gene set pathways when comparing patients with and without cancer. Nineteen gene sets were alternately regulated in both visceral and subcutaneous adipose tissues; however, eighteen of these were regulated in the opposite direction. Five pathways were significantly and alternately regulated in all 3 tissue types and included glycolysis/gluconeogenesis, ribosome, peroxisome proliferator activated receptor signaling, pathogenic Escherichia coli infection, and natural killer–mediated cytotoxicity. In the malignant endometrium, liver kinase B1 underexpression was observed in all patients with cancer. Liver kinase B1 underexpression decreased adenosine monophosphate–activated protein kinase activity toward acetyl-CoA carboxylase and implied enhanced lipid biosynthesis in obesity-induced endometrial cancer.

Conclusions Subcutaneous and visceral adipose tissue depots have opposite patterns of gene expression in obese patients with and without endometrial cancer. The altered de novo lipogenesis and individual gene targets identified provide new potential targets for cancer treatment and prevention for at-risk obese women.

  • Endometrial cancer
  • De novo lipogenesis
  • Obesity

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Footnotes

  • This work was funded by a grant from the University of Virginia Cancer Center through the Commonwealth Foundation for Cancer Research and the NCI Cancer Center Support Grant P30 CA44579.

  • The authors declare that there are no conflicts of interest.

  • This was presented in part as a poster at the 42nd annual meeting of the Society of Gynecologic Oncologists, March 2011.

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