Yujing J Heng1,2, Jun Wang3,4, Thomas U Ahearn5, Susan B Brown3, Xuehong Zhang6, Christine B Ambrosone7, Victor Piana de Andrade8, Adam M Brufsky9, Fergus J Couch10, Tari A King11, Francesmary Modugno12, Celine M Vachon13, Natalie C DuPre6, Montserrat Garcia-Closas5, Melissa A Troester14, David J Hunter6,15,16, A Heather Eliassen6,15, Rulla M Tamimi6,15, Susan E Hankinson3,6,15, Andrew H Beck17,18. 1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Dana 517B, Boston, MA, 02215, USA. yheng@bidmc.harvard.edu. 2. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA. yheng@bidmc.harvard.edu. 3. Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, USA. 4. Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA. 5. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 6. Channing Division of Network Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. 7. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA. 8. Departamento de Patologia, AC Camargo Cancer Center, São Paulo, Brazil. 9. Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 10. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 11. Dana-Farber Cancer Institute and Brigham and Women's Cancer Center, Boston, MA, USA. 12. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 13. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. 14. Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA. 15. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 16. Nuffield Department of Population Health, University of Oxford, Oxford, UK. 17. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Dana 517B, Boston, MA, 02215, USA. 18. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.
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.
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.
Entities:
Keywords:
Breast cancer; Gene expression; Nurses’ health study; Obesity; Polish breast cancer study; The cancer genome atlas
Authors: A Heather Eliassen; Graham A Colditz; Bernard Rosner; Walter C Willett; Susan E Hankinson Journal: JAMA Date: 2006-07-12 Impact factor: 56.272
Authors: Signe Borgquist; Elisabet Wirfält; Karin Jirström; Lola Anagnostaki; Bo Gullberg; Göran Berglund; Jonas Manjer; Göran Landberg Journal: Breast Cancer Res Date: 2007 Impact factor: 6.466
Authors: M García-Closas; L A Brinton; J Lissowska; N Chatterjee; B Peplonska; W F Anderson; N Szeszenia-Dabrowska; A Bardin-Mikolajczak; W Zatonski; A Blair; Z Kalaylioglu; G Rymkiewicz; D Mazepa-Sikora; R Kordek; S Lukaszek; M E Sherman Journal: Br J Cancer Date: 2006-06-06 Impact factor: 7.640
Authors: Rulla M Tamimi; Heather J Baer; Jonathan Marotti; Mark Galan; Laurie Galaburda; Yineng Fu; Anne C Deitz; James L Connolly; Stuart J Schnitt; Graham A Colditz; Laura C Collins Journal: Breast Cancer Res Date: 2008-08-05 Impact factor: 6.466
Authors: Natalie C DuPré; Yujing J Heng; Benjamin A Raby; Kimberly Glass; Jaime E Hart; Jen-Hwa Chu; Catherine Askew; A Heather Eliassen; Susan E Hankinson; Peter Kraft; Francine Laden; Rulla M Tamimi Journal: Environ Res Date: 2020-04-15 Impact factor: 6.498
Authors: Yujing J Heng; Susan E Hankinson; Jun Wang; Ludmil B Alexandrov; Christine B Ambrosone; Victor P de Andrade; Adam M Brufsky; Fergus J Couch; Tari A King; Francesmary Modugno; Celine M Vachon; A Heather Eliassen; Rulla M Tamimi; Peter Kraft Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-01-13 Impact factor: 4.254
Authors: Nita H Mukand; Naomi Y Ko; Nadia A Nabulsi; Colin C Hubbard; Brian C-H Chiu; Kent F Hoskins; Gregory S Calip Journal: Breast Cancer Date: 2021-11-19 Impact factor: 4.239
Authors: Jae H Kang; Cheng Peng; Jinnie J Rhee; Maryam S Farvid; Walter C Willett; Frank B Hu; Bernard A Rosner; Rulla Tamimi; A Heather Eliassen Journal: Am J Clin Nutr Date: 2020-12-10 Impact factor: 7.045
Authors: Cheng Peng; Yujing J Heng; Donghao Lu; Natalie C DuPre; Kevin H Kensler; Kimberly Glass; Oana A Zeleznik; Peter Kraft; David Feldman; Susan E Hankinson; Kathryn Rexrode; A Heather Eliassen; Rulla M Tamimi Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-04-01 Impact factor: 4.254
Authors: Jun Wang; Cheng Peng; Catherine Guranich; Yujing J Heng; Gabrielle M Baker; Christopher A Rubadue; Kimberly Glass; A Heather Eliassen; Rulla M Tamimi; Kornelia Polyak; Susan Hankinson Journal: J Natl Cancer Inst Date: 2021-06-01 Impact factor: 11.816
Authors: Rachel A Sabol; Vidal A Villela; Alexandra Denys; Benjamin T Freeman; Alifiani B Hartono; Rachel M Wise; Mark A A Harrison; Maxwell B Sandler; Fokhrul Hossain; Lucio Miele; Bruce A Bunnell Journal: Int J Mol Sci Date: 2020-04-15 Impact factor: 5.923
Authors: Cheng Peng; Natalie DuPre; Trang VoPham; Yujing J Heng; Gabrielle M Baker; Christopher A Rubadue; Kimberly Glass; Abhijeet Sonawane; Oana Zeleznik; Peter Kraft; Susan E Hankinson; A Heather Eliassen; Jaime E Hart; Francine Laden; Rulla M Tamimi Journal: BMC Cancer Date: 2020-07-28 Impact factor: 4.430