TY - JOUR
T1 - Energy balance modulation impacts epigenetic reprogramming, ERa and ERb expression, and mammary tumor development in MMTV-neu transgenic mice
AU - Rossi, Emily L.
AU - Dunlap, Sarah M.
AU - Bowers, Laura W.
AU - Khatib, Subreen A.
AU - Doerstling, Steven S.
AU - Smith, Laura A.
AU - Ford, Nikki A.
AU - Holley, Darcy
AU - Brown, Powel H.
AU - Estecio, Marcos R.
AU - Kusewitt, Donna F.
AU - DeGraffenried, Linda A.
AU - Bultman, Scott J.
AU - Hursting, Stephen D.
N1 - Funding Information:
This study was supported by the American Institute for Cancer Research (8A049), Breast Cancer Research Foundation, and R35 (CA197627) from the NCI. The mouse RNA-seq and methylation analysis was supported by the UT-MD Anderson Cancer Center Science Park NGS Core, supported by CPRIT Core Facility Support Grant RP120348. E.L. Rossi and L.W. Bowers were supported by a training grant from the NCI (R25CA057726), S.M. Dunlap was supported by a USAMRMC Breast Cancer Research Program Postdoctoral Fellowship (W81XWH-09-1-0720), and N.A. Ford was supported by an American Institute for Cancer Research Postdoctoral Fellowship.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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, overweightinducing, 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 dietinduced 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 of ESR1 and ESR2, consistent with sustained transcriptional activation of ERα and ERβ. Mammary expression of the DNA methylation enzyme DNMT1 was 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.
AB - 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, overweightinducing, 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 dietinduced 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 of ESR1 and ESR2, consistent with sustained transcriptional activation of ERα and ERβ. Mammary expression of the DNA methylation enzyme DNMT1 was 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.
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U2 - 10.1158/0008-5472.CAN-16-2795
DO - 10.1158/0008-5472.CAN-16-2795
M3 - Article
C2 - 28373182
AN - SCOPUS:85018369291
SN - 0008-5472
VL - 77
SP - 2500
EP - 2511
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -