Obesity-Associated Alterations in Inflammation, Epigenetics, and Mammary Tumor Growth Persist in Formerly Obese Mice

Abstract

Using a murine model of basal-like breast cancer, we tested the hypothesis that chronic obesity, an established breast cancer risk and progression factor in women, induces mammary gland epigenetic reprogramming and increases mammary tumor growth. Moreover, we assessed whether the obesity-induced epigenetic and protumor effects are reversed by weight normalization. Ovariectomized female C57BL/6 mice were fed a control diet or diet-induced obesity (DIO) regimen for 17 weeks, resulting in a normal weight or obese phenotype, respectively. Mice on the DIO regimen were then randomized to continue the DIO diet or were switched to the control diet, resulting in formerly obese (FOb) mice with weights comparable to control mice. At week 24, all mice were orthotopically injected with MMTV-Wnt-1 mouse mammary tumor cells. Mean tumor volume, serum IL-6 levels, expression of pro-inflammatory genes in the mammary fat pad, and mammary DNA methylation profiles were similar in DIO and FOb mice, and higher than in controls. Many of the genes found to have obesity-associated hypermethylation in mice were also found to be hypermethylated in the normal breast tissue of obese versus non-obese human subjects, and nearly all of these concordant genes remained hypermethylated after significant weight loss in the FOb mice. Our findings suggest that weight normalization may not be sufficient to reverse the effects of chronic obesity on epigenetic reprogramming and inflammatory signals in the microenvironment that are associated with breast cancer progression.

Young Adult Cancer: Influence of the Obesity Pandemic

“…Metformin, extensively used for treatment of type 2 diabetes mellitus, has already been shown, at low dose, to be safe and reduce recurrence of colorectal adenoma in nondiabetic patients following initial polyp resection . Because obesity‐promoted cancers have been shown in some cases to involve epigenetic changes , other potential opportunities for chemoprevention in young adults include the use of epigenetic targeted therapies .…”

Highlights from the 15th St Gallen International Breast Cancer Conference 15–18 March, 2017, Vienna: tailored treatments for patients with early breast cancer

“…Though currently there are no data supporting the benefit of lifestyle habits in improving BC outcomes [7]. However, there are ongoing trials (e.g.…”

Energy Balance Modulation Impacts Epigenetic Reprogramming, ERα and ERβ Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice

“…We and others have shown that obesity can induce aberrant DNA methylation of genes involved in growth factor and inflammatory signaling (29, 40). To assess whether the energy balance-dependent effects on ERα and ERβ expression are controlled epigenetically, we characterized epigenetic alterations in mammary tissue DNA from baseline mice, from CR and OW mice after 5 months on diet, and from survival study mice after 14 to 22 months of diet.…”

“…Library preparation and sequencing for baseline, CR and OW in the 5-month time point and survival study were performed at UT MD Anderson Cancer Center’s DNA Methylation Analysis Core and Science Park Next-Generation Sequencing Facility, according to published protocols as previously described (29) (Supplementary Table S1). Samples from DIO mice were not analyzed given the cost of RRBS and the similarities between OW and DIO mice in ERα and ERβ mRNA and protein expression.…”