title: Energy Balance Modulation Impacts Epigenetic Reprogramming, ERα and ERβ Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice.
abstract: The association between obesity and breast cancer risk and prognosis is well established in estrogen receptor (ER)-positive disease but less clear in HER2-positive disease. Here, we report preclinical evidence suggesting weight maintenance through calorie restriction (CR) may limit risk of HER2-positive breast cancer. In female MMTV-HER2/neu transgenic mice, we found that ERα and ERβ expression, mammary tumorigenesis, and survival are energy balance dependent in association with epigenetic reprogramming. Mice were randomized to receive a CR, overweight-inducing, or diet-induced obesity regimen (n= 27/group). Subsets of mice (n= 4/group/time point) were euthanized after 1, 3, and 5 months to characterize diet-dependent metabolic, transcriptional, and epigenetic perturbations. Remaining mice were followed up to 22 months. Relative to the overweight and diet-induced obesity regimens, CR decreased body weight, adiposity, and serum metabolic hormones as expected and also elicited an increase in mammary ERα and ERβ expression. Increased DNA methylation accompanied this pattern, particularly at CpG dinucleotides located within binding or flanking regions for the transcriptional regulator CCCTC-binding factor ofESR1andESR2,consistent with sustained transcriptional activation of ERα and ERβ. Mammary expression of the DNA methylation enzymeDNMT1was stable in CR mice but increased over time in overweight and diet-induced obesity mice, suggesting CR obviates epigenetic alterations concurrent with chronic excess energy intake. In the survival study, CR elicited a significant suppression in spontaneous mammary tumorigenesis. Overall, our findings suggest a mechanistic rationale to prevent or reverse excess body weight as a strategy to reduce HER2-positive breast cancer risk.Cancer Res; 77(9); 2500-11. ©2017 AACR.
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Rossi
authors.affiliation: Department of Nutritional Sciences, University of Texas, Austin, Texas.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dunlap
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Bowers
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Subreen A
authors.initials: SA
authors.lastname: Khatib
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Doerstling
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Smith
authors.affiliation: Department of Nutritional Sciences, University of Texas, Austin, Texas.
authors.forename: Nikki A
authors.initials: NA
authors.lastname: Ford
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Darcy
authors.initials: D
authors.lastname: Holley
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Breast Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Marcos R
authors.initials: MR
authors.lastname: Estecio
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Donna F
authors.initials: DF
authors.lastname: Kusewitt
authors.affiliation: Department of Nutritional Sciences, University of Texas, Austin, Texas.
authors.forename: Linda A
authors.initials: LA
authors.lastname: deGraffenried
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bultman
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. hursting@email.unc.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology; D031204:Caloric Restriction; D063646:Carcinogenesis / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D012307:Risk Factors
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse