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Oncoimmunology. 2017 Aug 10;6(11):e1356142. doi: 10.1080/2162402X.2017.1356142. eCollection 2017.

Age, estrogen, and immune response in breast adenocarcinoma and adjacent normal tissue.

Author information

1
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
2
K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
3
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
4
Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, California, USA.
5
Department of Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital, Lørenskog, Norway.
6
Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
7
Department of Surgery, Oslo University Hospital, Ullevål, Oslo, Norway.
8
Department of Breast-Endocrine Surgery, Surgical Division, Akershus University Hospital, Lørenskog, Norway.

Abstract

Chronic inflammation promotes breast tumor growth and invasion by accelerating angiogenesis and tissue remodeling in the tumor microenvironment. There is a complex relationship between inflammation and estrogen, which drives the growth of 70 percent of breast tumors. While low levels of estrogen exposure stimulate macrophages and other inflammatory cell populations, very high levels are immune suppressive. Breast tumor incidence is increased by obesity and age, which interact to influence inflammatory cell populations in normal breast tissue. To characterize the impact of these factors on tumors and the tumor microenvironment, we measured gene expression in 195 breast adenocarcinomas and matched adjacent normal breast tissue samples collected at Akershus University Hospital (AHUS). Age and Body Mass Index (BMI) were independently associated with inflammation in adjacent normal tissue but not tumors. Estrogen Receptor (ER)-negative tumors had elevated macrophage expression compared with matched normal tissue, but ER-positive tumors showed an unexpected decrease in macrophage expression. We found an inverse relationship between the increase in tumor estrogen pathway expression compared with adjacent normal tissue and tumor macrophage score. We validated this finding in 126 breast tumor-normal pairs from the previously published METABRIC cohort. We developed a novel statistic, the Rewiring Coefficient, to quantify the rewiring of gene co-expression networks at the level of individual genes. Differential correlation analysis demonstrated distinct pathways were rewired during tumorigenesis. Our data support an immune suppressive effect of high doses of estrogen signaling in breast tumor microenvironment, suggesting that this effect contributes to the greater presence of prognostic and therapeutically relevant immune cells in ER-negative tumors.

KEYWORDS:

age; breast cancer; cytotoxic lymphocyte; estrogen; gene expression; inflammation; obesity; tumor microenvironment

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