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Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression

ABSTRACT: Activation of inflammatory pathways is one plausible mechanism underlying the association between obesity and increased breast cancer risk. However, macrophage infiltration and local biomarkers of inflammation in breast adipose tissue have seldom been studied in association with obesity. Gene expression profiles of normal breast tissue from reduction mammoplasty patients were evaluated by whole genome microarrays to identify patterns associated with obesity status (normal-weight, body mass index (BMI) <25; overweight, BMI 25-29.9; obese, BMI > or equal to 30). The presence of macrophage-enriched inflammatory loci with immunopositivity for CD68 protein was evaluated by immunohistochemistry (IHC). After adjusting for confounding by age, 760 genes were differentially expressed (203 up and 557 down; FDR = 0.026) between normal-weight and obese women. Gene ontology analysis suggested significant enrichment for pathways involving IL-6, IL-8, CCR5 signaling in macrophages and RXRalpha and PPARalpha activation, consistent with a pro-inflammatory state and suggestive of macrophage infiltration. Gene set enrichment analysis also demonstrated that the genomic signatures of monocytes and macrophages were over-represented in the obese group with FDR of 0.08 and 0.13, respectively. Increased macrophage infiltration was confirmed by IHC, which showed that the breast adipose tissue of obese women had higher average macrophage counts (mean = 8.96 vs. 3.56 in normal-weight women) and inflammatory foci counts (mean = 4.91 vs. 2.67 in normal-weight women). Obesity is associated with local inflammation and macrophage infiltration in normal human breast adipose tissues. Given the role of macrophages in carcinogenesis, these findings have important implications for breast cancer etiology and progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE33526 | GEO | 2011/11/08

SECONDARY ACCESSION(S): PRJNA148793

REPOSITORIES: GEO

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Project description:Background: Obesity is a risk factor for breast cancer in postmenopausal women and is associated with decreased survival and less favorable clinical characteristics such as greater tumor burden, higher grade, and poor prognosis, regardless of menopausal status. Despite the negative impact of obesity on clinical outcome, molecular mechanisms through which excess adiposity influences breast cancer etiology are not well-defined. Methods: Affymetrix U133 2.0 gene expression data were generated for 405 primary breast tumors using RNA isolated from laser microdissected tissues. Patients were classified as normal-weight (BMI<25), overweight (BMI 25-29.9) or obese (BMI>30). Statistical analysis was performed by ANOVA using Partek Genomics Suite version 6.6 using a false discovery rate <0.05 to define significance. Results: Obese patients were significantly more likely to be diagnosed >50 years or with African American ancestry compared to lean or overweight women. Pathological characteristics, including tumor stage, size or grade, lymph node status, intrinsic subtype, and breast cancer mortality did not differ significantly between groups. No significant gene expression differences were detected by BMI In a non-stratified analysis which included all subtypes or within luminal B, HER2-enriched or basal-like subtypes. Within luminal A tumors, however, 84 probes representing 77 genes from pathways such as cell cycle, p53 and mTOR signaling, tight junctions and a number of cancer associated pathways were differentially expressed. Conclusions: Identification of transcriptome differences in luminal A tumors from normal-weight compared to obese women suggests that obesity alters gene expression within ER+ tumor epithelial cells. Alterations of pathways involved in cell cycle control, tumorigenesis and metabolism may promote cellular proliferation and provide a molecular explanation for less favorable outcome of obese women with breast cancer. Targeted treatments, such as mTOR inhibitors, may allow for improved treatment and survival of obese women, especially African American women, who are more likely to be obese and suffer outcome disparities.

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Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression

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