Jun Wang1,2, Cheng Peng3, Catherine Guranich4, Yujing J Heng5,6, Gabrielle M Baker5, Christopher A Rubadue5, Kimberly Glass3, A Heather Eliassen3,7, Rulla M Tamimi3,7,8, Kornelia Polyak9,10, Susan Hankinson3,4. 1. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 2. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. 3. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 4. Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, USA. 5. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 6. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA. 7. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 8. Department of Healthcare Policy and Research, Weill Cornell Medicine, USC, New York, NY, USA. 9. Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA. 10. Department of Medicine, Harvard Medical School, Boston, MA, USA.
Abstract
BACKGROUND: Cumulative epidemiologic evidence has shown that early-life adiposity is strongly inversely associated with breast cancer risk throughout life, independent of adult obesity. However, the molecular mechanisms remain poorly understood. METHODS: We assessed the association of early-life adiposity, defined as self-reported body size during ages 10-20 years from a validated 9-level pictogram, with the transcriptome of breast tumor (N = 835) and tumor-adjacent histologically normal tissue (N = 663) in the Nurses' Health Study. We conducted multivariable linear regression analysis to identify differentially expressed genes in tumor and tumor-adjacent tissue, respectively. Molecular pathway analysis using Hallmark gene sets (N = 50) was further performed to gain biological insights. Analysis was stratified by tumor estrogen receptor (ER) protein expression status (n = 673 for ER+ and 162 for ER- tumors). RESULTS: No gene was statistically significantly differentially expressed by early-life body size after multiple comparison adjustment. However, pathway analysis revealed several statistically significantly (false discovery rate < 0.05) upregulated or downregulated gene sets. In stratified analyses by tumor ER status, larger body size during ages 10-20 years was associated with decreased cellular proliferation pathways, including MYC target genes, in both ER+ and ER- tumors. In ER+ tumors, larger body size was also associated with upregulation in genes involved in TNFα/NFkB signaling. In ER- tumors, larger body size was additionally associated with downregulation in genes involved in interferon α and interferon γ immune response and Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling; the INFγ response pathway was also downregulated in ER- tumor-adjacent tissue, though at borderline statistical significance (false discovery rate = 0.1). CONCLUSIONS: These findings provide new insights into the biological and pathological underpinnings of the early-life adiposity and breast cancer association.
BACKGROUND: Cumulative epidemiologic evidence has shown that early-life adiposity is strongly inversely associated with breast cancer risk throughout life, independent of adult obesity. However, the molecular mechanisms remain poorly understood. METHODS: We assessed the association of early-life adiposity, defined as self-reported body size during ages 10-20 years from a validated 9-level pictogram, with the transcriptome of breast tumor (N = 835) and tumor-adjacent histologically normal tissue (N = 663) in the Nurses' Health Study. We conducted multivariable linear regression analysis to identify differentially expressed genes in tumor and tumor-adjacent tissue, respectively. Molecular pathway analysis using Hallmark gene sets (N = 50) was further performed to gain biological insights. Analysis was stratified by tumor estrogen receptor (ER) protein expression status (n = 673 for ER+ and 162 for ER- tumors). RESULTS: No gene was statistically significantly differentially expressed by early-life body size after multiple comparison adjustment. However, pathway analysis revealed several statistically significantly (false discovery rate < 0.05) upregulated or downregulated gene sets. In stratified analyses by tumor ER status, larger body size during ages 10-20 years was associated with decreased cellular proliferation pathways, including MYC target genes, in both ER+ and ER- tumors. In ER+ tumors, larger body size was also associated with upregulation in genes involved in TNFα/NFkB signaling. In ER- tumors, larger body size was additionally associated with downregulation in genes involved in interferon α and interferon γ immune response and Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling; the INFγ response pathway was also downregulated in ER- tumor-adjacent tissue, though at borderline statistical significance (false discovery rate = 0.1). CONCLUSIONS: These findings provide new insights into the biological and pathological underpinnings of the early-life adiposity and breast cancer association.
Authors: Meera Sangaramoorthy; Amanda I Phipps; Pamela L Horn-Ross; Jocelyn Koo; Esther M John Journal: Cancer Epidemiol Biomarkers Prev Date: 2011-11-04 Impact factor: 4.254
Authors: Erica T Warner; Rong Hu; Laura C Collins; Andrew H Beck; Stuart Schnitt; Bernard Rosner; A Heather Eliassen; Karin B Michels; Walter C Willett; Rulla M Tamimi Journal: Cancer Prev Res (Phila) Date: 2016-09
Authors: Fiona C McGillicuddy; Elise H Chiquoine; Christine C Hinkle; Roy J Kim; Rachana Shah; Helen M Roche; Emer M Smyth; Muredach P Reilly Journal: J Biol Chem Date: 2009-09-23 Impact factor: 5.157