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Breast Cancer Research and Treatment

, Volume 173, Issue 3, pp 667–677 | Cite as

Molecular mechanisms linking high body mass index to breast cancer etiology in post-menopausal breast tumor and tumor-adjacent tissues

  • Yujing J. HengEmail author
  • Jun Wang
  • Thomas U. Ahearn
  • Susan B. Brown
  • Xuehong Zhang
  • Christine B. Ambrosone
  • Victor Piana de Andrade
  • Adam M. Brufsky
  • Fergus J. Couch
  • Tari A. King
  • Francesmary Modugno
  • Celine M. Vachon
  • Natalie C. DuPre
  • Montserrat Garcia-Closas
  • Melissa A. Troester
  • David J. Hunter
  • A. Heather Eliassen
  • Rulla M. Tamimi
  • Susan E. Hankinson
  • Andrew H. Beck
Epidemiology

Abstract

Purpose

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.

Methods

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).

Results

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.

Conclusions

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.

Keywords

Breast cancer Obesity Gene expression The cancer genome atlas Nurses’ health study Polish breast cancer study 

Notes

Acknowledgements

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.

Author contributions

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

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

Competing interests

AHB is an equity stock holder and Board of Director Member of PathAI. All other authors declare no competing interests.

Ethics approval

The Committee on the Use of Human Subjects in Research at Brigham and Women’s Hospital, Boston, MA reviewed and approved this study.

Supplementary material

10549_2018_5034_MOESM1_ESM.doc (44 kb)
Supplementary material 1 (DOC 44 KB) Detailed description of methodologies.
10549_2018_5034_MOESM2_ESM.doc (167 kb)
Supplementary material 2 (DOC 167 KB)
10549_2018_5034_MOESM3_ESM.pdf (665 kb)
Supplementary material 3 (PDF 664 KB) Heatmaps displaying driver genes (p<0.10, limma analyses) that are contributing to the enrichment of the validated gene sets in A. estrogen receptor-positive tumors, B. estrogen receptor-negative tumors, C. estrogen receptor-positive tumor-adjacent tissues and D. estrogen receptor-negative tumor-adjacent tissues. Increasing color intensity of the cells indicates a smaller p value.
10549_2018_5034_MOESM4_ESM.pdf (143 kb)
Supplementary material 4 (PDF 143 KB) Questionnaire provided to The Cancer Genome Atlas (TCGA) participants to collect lifestyle variables.
10549_2018_5034_MOESM5_ESM.xlsx (49.3 mb)
Supplementary material 5 (XLSX 50498 KB) Detailed differential gene expression analyses using limma.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Yujing J. Heng
    • 1
    • 2
    Email author
  • Jun Wang
    • 3
    • 4
  • Thomas U. Ahearn
    • 5
  • Susan B. Brown
    • 3
  • Xuehong Zhang
    • 6
  • Christine B. Ambrosone
    • 7
  • Victor Piana de Andrade
    • 8
  • Adam M. Brufsky
    • 9
  • Fergus J. Couch
    • 10
  • Tari A. King
    • 11
  • Francesmary Modugno
    • 12
  • Celine M. Vachon
    • 13
  • Natalie C. DuPre
    • 6
  • Montserrat Garcia-Closas
    • 5
  • Melissa A. Troester
    • 14
  • David J. Hunter
    • 6
    • 15
    • 16
  • A. Heather Eliassen
    • 6
    • 15
  • Rulla M. Tamimi
    • 6
    • 15
  • Susan E. Hankinson
    • 3
    • 6
    • 15
  • Andrew H. Beck
    • 1
    • 2
  1. 1.Department of Pathology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Cancer Research InstituteBeth Israel Deaconess Cancer CenterBostonUSA
  3. 3.Department of Biostatistics and Epidemiology, School of Public Health and Health SciencesUniversity of Massachusetts AmherstAmherstUSA
  4. 4.Department of Preventive MedicineUniversity of Southern CaliforniaLos AngelesUSA
  5. 5.Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaUSA
  6. 6.Channing Division of Network Medicine, Department of Medicine, Harvard Medical SchoolBrigham and Women’s HospitalBostonUSA
  7. 7.Department of Cancer Prevention and ControlRoswell Park Cancer InstituteBuffaloUSA
  8. 8.Departamento de PatologiaAC Camargo Cancer CenterSão PauloBrazil
  9. 9.Department of MedicineUniversity of Pittsburgh Medical CenterPittsburghUSA
  10. 10.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  11. 11.Dana-Farber Cancer Institute and Brigham and Women’s Cancer CenterBostonUSA
  12. 12.Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of Pittsburgh School of MedicinePittsburghUSA
  13. 13.Department of Health Sciences ResearchMayo ClinicRochesterUSA
  14. 14.Department of EpidemiologyUniversity of North CarolinaChapel HillUSA
  15. 15.Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonUSA
  16. 16.Nuffield Department of Population HealthUniversity of OxfordOxfordUK

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