Comprehensive molecular characterization of surgical vs. dietary weight loss: impact on mammary tumor burden

Background: Obesity is a widespread health concern and established risk factor for basal-like breast cancer. However, studies are conflicted on the benefits of weight loss relevant to breast cancer prevention. Recent studies suggest that certain methods of robust weight loss with long-term maintenance, such as bariatric surgery, might in fact be able to reverse obesity-associated breast cancer risk. Hypothesis: We hypothesize that weight loss by sleeve gastrectomy will generate sufficient metabolic normalization to reverse obesity-driven mammary tumor burden more effectively than weight loss by diet alone. Methods: Mice were fed a low-fat control (CON) or high-fat diet-induced obesity (DIO) regimen for 15 weeks to model chronic obesity. DIO mice were randomized to continue on a high-fat diet (Obese) or undergo weight loss by either sleeve gastrectomy (~70% excision of the stomach) in combination with switching to a low-fat diet or by switching to a low-fat diet alone, resulting in formerly obese (FOB)-Surg and FOB-Diet mice, respectively. Additionally, a subset of normal weight (NW) Control mice (Con, n=25) was maintained on a low-fat diet throughout the study. NW Control, FOB-Diet, and Obese mice underwent a sham procedure to control for the insult of surgery. FOB-Surg and FOB-Diet mice did not lose a significantly different amount of weight and body fat; both groups had significantly lower weight and percent body fat than Obese mice. Eight weeks after surgical procedures and diet switches, all mice on study were orthotopically injected with E0771 mammary tumor cells, which model BLBC. Results: At the end of study, ex vivo tumor volume in FOB-Surg mice was not significantly different from NW Control mice and significantly different from Obese mice. However, tumor volume in FOB-Diet mice was significantly different from NW Control mice and not significantly different from Obese mice. In addition, FOB-Surg mice had levels of serum tumor necrosis factor-alpha (TNF-a), insulin, and mammary adipocyte size that were not significantly different from NW Control mice and significantly different from FOB-Diet and Obese mice. Lastly, pathway analysis of mammary tissue gene expression revealed redundant upregulation of genes in extracellular matrix remodeling and growth factor signaling in Obese vs. FOB-Surg and FOB-Diet vs. FOB-Surg mice. Conclusions: Our results demonstrate that surgical weight loss imparted a plurality of metabolic advantages, functional genomic changes, and successful reversal of obesity-associated mammary tumor burden that were not similarly achieved by dietary weight loss.Bachelor of Science in Public Healt

Obesity and Cancer Metabolism: A Perspective on Interacting Tumor–Intrinsic and Extrinsic Factors

Obesity is associated with increased risk and poor prognosis of many types of cancers. Several obesity-related host factors involved in systemic metabolism can influence tumor initiation, progression, and/or response to therapy, and these have been implicated as key contributors to the complex effects of obesity on cancer incidence and outcomes. Such host factors include systemic metabolic regulators including insulin, insulin-like growth factor 1, adipokines, inflammation-related molecules, and steroid hormones, as well as the cellular and structural components of the tumor microenvironment, particularly adipose tissue. These secreted and structural host factors are extrinsic to, and interact with, the intrinsic metabolic characteristics of cancer cells to influence their growth and spread. This review will focus on the interplay of these tumor cell–intrinsic and extrinsic factors in the context of energy balance, with the objective of identifying new intervention targets for preventing obesity-associated cancer

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

The association between obesity and breast cancer risk and prognosis is well established in ER-positive disease but less clear in HER2-positive disease. Here, we report preclinical evidence suggesting weight maintenance through calorie restriction 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 calorie restriction (CR), overweight (OW)-inducing, or diet-induced obesity (DIO) 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 OW and DIO 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 (CTCF) 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 OW and DIO 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

Growth differentiation factor 15 in a community-based sample : age-dependent reference limits and prognostic impact

Background: Despite the growing body of evidence on growth differentiation factor 15 (GDF-15) reference values for patients with existing cardiovascular disease, limited investigation has been dedicated to characterizing the distribution and prognostic impact of GDF-15 in predominantly healthy populations. Furthermore, current cutoff values for GDF-15 fail to account for the well-documented age-dependence of circulating GDF-15. Methods: From 810 community-dwelling older adults, we selected a group of apparently healthy participants (n = 268). From this sample, circulating GDF-15 was modeled using the generalized additive models for location scale and shape (GAMLSS) to develop age-dependent centile values. Unadjusted and adjusted Cox proportional hazards models were used to assess the association between the derived GDF-15 reference values (expressed as centiles) and all-cause mortality. Results: Smoothed centile curves showed increasing GDF-15 with age in the apparently healthy participants. An approximately three-fold difference was observed between the 95th and 5th GDF-15 centiles across ages. In a median 8.0 years of follow-up, 97 all-cause deaths were observed in 806 participants with eligible values. In unadjusted Cox regression analyses, the hazard ratio (95% CI) for all-cause mortality per 25-unit increase in GDF-15 centile was 1.80 (1.48-2.20) and dichotomized at the 95th centile, >= 95th versus <95th, was 3.04 (1.99-4.65). Age-dependent GDF-15 centiles remained a significant predictor of all-cause mortality in all subsequent adjusted models. Conclusions: Age-dependent GDF-15 centile values developed from a population of apparently healthy older adults are independently predictive of all-cause mortality. Therefore, GDF-15 reference values could be a useful tool for risk-stratification in a clinical setting

Leptin signaling mediates obesity-associated CSC enrichment and EMT in preclinical TNBC models

© 2018 American Association for Cancer Research. Obesity is associated with poor prognosis in triple-negative breast cancer (TNBC). Preclinical models of TNBC were used to test the hypothesis that increased leptin signaling drives obesity-associated TNBC development by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). MMTV-Wnt-1 transgenic mice, which develop spontaneous basal-like, triple-negative mammary tumors, received either a control diet (10% kcal from fat) or a diet-induced obesity regimen (DIO, 60% kcal from fat) for up to 42 weeks (n ¼ 15/group). Mice were monitored for tumor development and euthanized when tumor diameter reached 1.5 cm. Tumoral gene expression was assessed via RNA sequencing (RNA-seq). DIO mice had greater body weight and percent body fat at termination than controls. DIO mice, versus controls, demonstrated reduced survival, increased systemic metabolic and inflammatory perturbations, upregulated tumoral CSC/EMT gene signature, elevated tumoral aldehyde dehydrogenase activity (a CSC marker), and greater leptin signaling. In cell culture experiments using TNBC cells (murine: E-Wnt and M-Wnt; human: MDA-MB-231), leptin enhanced mammosphere formation, and media supplemented with serum from DIO versus control mice increased cell viability, migration, invasion, and CSC- and EMT-related gene expression, including Foxc2, Twist2, Vim, Akt3, and Sox2. In E-Wnt cells, knockdown of leptin receptor ablated these procancer effects induced by DIO mouse serum. These findings indicate that increased leptin signaling is causally linked to obesity-associated TNBC development by promoting CSC enrichment and EMT. Implications: Leptin-associated signals impacting CSC and EMT may provide new targets and intervention strategies for decreasing TNBC burden in obese women