Molecular mechanisms linking high body mass index to breast cancer etiology in post-menopausal breast tumor and tumor-adjacent tissues
In post-menopausal women, high body mass index (BMI) is an established breast cancer risk factor and is associated with worse breast cancer prognosis. We assessed the associations between BMI and gene expression of both breast tumor and adjacent tissue in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER−) diseases to help elucidate the mechanisms linking obesity with breast cancer biology in 519 post-menopausal women from the Nurses’ Health Study (NHS) and NHSII.
Differential gene expression was analyzed separately in ER+ and ER− disease both comparing overweight (BMI ≥ 25 to < 30) or obese (BMI ≥ 30) women to women with normal BMI (BMI < 25), and per 5 kg/m2 increase in BMI. Analyses controlled for age and year of diagnosis, physical activity, alcohol consumption, and hormone therapy use. Gene set enrichment analyses were performed and validated among a subset of post-menopausal cases in The Cancer Genome Atlas (for tumor) and Polish Breast Cancer Study (for tumor-adjacent).
No gene was differentially expressed by BMI (FDR < 0.05). BMI was significantly associated with increased cellular proliferation pathways, particularly in ER+ tumors, and increased inflammation pathways in ER− tumor and ER− tumor-adjacent tissues (FDR < 0.05). High BMI was associated with upregulation of genes involved in epithelial-mesenchymal transition in ER+ tumor-adjacent tissues.
This study provides insights into molecular mechanisms of BMI influencing post-menopausal breast cancer biology. Tumor and tumor-adjacent tissues provide independent information about potential mechanisms.
KeywordsBreast cancer Obesity Gene expression The cancer genome atlas Nurses’ health study Polish breast cancer study
We thank the participants and staff of the NHS and the NHSII for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. We are also grateful to the participants of TCGA and PBCS.
Conceived and designed the study: SEH, AHB, AHE, RMT, DJH. Nurses’ Health Studies microarray, data collection, and analyses: YJH, JW, XZ, NCD, AHE, RMT, SEH, AHB. The Cancer Genome Atlas data collection: SBB, CBA, VPA, AMB, FJC, TAK, FM, CMV. Polish Breast Cancer Study data collection and analyses: TUA, MGC, MAT. All authors contributed to the writing and reviewing of the manuscript.
Funding for this project was provided by the National Institutes of Health Grants U19 CA148065, UM1 CA186107, P01 CA87969, UM1 CA176726, and R01 CA166666; the National Institute of Health Epidemiology Education Training Grant (T32 CA09001 to NCD); the National Library of Medicine Career Development Award (K22LM011931 to AHB); Susan G. Komen (SAC110014 to SEH; CCR 14302670 to AHB); the Klarman Family Foundation (YJH and AHB); and the University of Pittsburgh School of Medicine Dean’s Faculty Advancement Award (FM). Funds from the National Institutes of Health Intramural Research Program supported the Polish Breast Cancer Study and work by MGC and TUA.
Compliance with ethical standards
AHB is an equity stock holder and Board of Director Member of PathAI. All other authors declare no competing interests.
The Committee on the Use of Human Subjects in Research at Brigham and Women’s Hospital, Boston, MA reviewed and approved this study.
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