Breast cancer (BC) has surpassed lung cancer as the most commonly diagnosed cancer among women in the US, as well as globally. A number of factors evidently contribute to the risk of developing BC, including age, physical activity, overweight/obesity, alcohol consumption, etc. It is of particular importance to study the role of body fatness and its potential influence on the risk of developing BC, as the number of individuals with obesity has increased with an alarming rate worldwide in recent decades. Epigenetics alterations are reversible, and do not alter the DNA sequence; however, they can affect gene expression via modifiable factors, including lifestyle and environmental factors. The present review article, in addition to providing overall reviews of obesity and BC in association with public health, concentrated on the epigenetic phenomena, with a focus on the well-studied DNA methylation, and its role in the association between obesity and BC. The present review aimed to provide insight into the understanding of the paradoxical effects of obesity on pre-vs. post-menopausal BC (pre-BC vs. post-BC), and describe the mechanisms through which folate metabolism/DNA methylation may be responsible for the protective effects of obesity on pre-BC. The literature presented in the present review article indicates that the epigenetic alterations represent a mediator in the association between obesity and BC; however, the mechanisms through which obesity differentially affects pre-vs. post-BC remain unclear. Further studies using animal models and the analyses of human tissue biopsies are thus required to delineate the paradoxical effects of obesity on BC. Contents1. Obesity and breast cancer 2. Epigenetic alterations in breast cancer 3. Obesity and DNA methylation 4. Obesity, DNA methylation and breast cancer 5. Folate metabolism in obesity and breast cancer 6. Conclusions and future perspectives Obesity and breast cancerPrevalence of breast cancer (BC). BC has surpassed lung cancer as the most commonly diagnosed type of cancer among women, with ~2.26 million new cases and ~685,000 deaths recorded globally in 2020. These numbers represent 24.5% of all new cancer cases and 15.5% of cancer-attributed mortality in women, respectively (1). In the US, the new cases of BC have also markedly increased, reaching top levels among all new cancer cases among women, with ~282,000 cases estimated in 2021 (30%); BC also represents the 2nd leading cause of cancer-related mortality, with 43,600 deaths (15%), coming only second following lung cancer (2).The BC incidence rates have consistently increased during the decades between 1970-2000 in a number of industrialized countries, likely reflecting changes in lifestyle associated with civilization and increased detection via mammographic screening. In the 2000s, the incidence rates had reached a
Scope The previous study shows that obesity‐promoted inflammation is responsible for the activation of the intestinal tumorigenic Wnt‐signaling. The present study aims to test a dietary strategy, dietary supplementation with a high dose of vitamin D (VD) or its combination with sulforaphane (SFN) to inhibit intestinal inflammation and obesity‐associated tumorigenesis. Methods and results Apc1638N mice are randomly divided into four groups: LF, a low‐fat diet (10 kcal% fat) with 200 IU VD; HF, a high‐fat diet (60 kcal% fat) with 200 IU VD; HFD, a high‐fat diet with 5000 IU VD; and HFDS, a high‐fat diet plus 5000 IU VD and 0.23 g SFN per ≈4000 kcal. VD administration decreased tumor incidence and size, and the co‐administration with SFN (HFDS) magnified the effects. Inflammation and Wnt‐signaling are suppressed by VD. The addition of SFN decreased the activity of histone deacetylase (HDAC) and increased autophagy. Conclusion The administration of VD, at 5000 IU level, exerts an anti‐inflammatory property and leads to suppressed intestinal Wnt‐signaling and tumorigenesis in obese mice. The molecular function of SFN on a high dose of VD supplementation, although displayed on the inhibition of HDAC and the activation of autophagy, needs further investigation.
Obesity is an established risk factor for colorectal cancer (CRC), but the mechanism(s) responsible for this relationship are still not fully understood. We hypothesize that obesity creates a low‐grade colonic inflammatory microenvironment, which facilitates the development of CRC. Our prior study suggested tumor necrosis factor alpha (TNF‐α) might elevate the Wnt‐signaling, and thereby promote the colonic tumorigenesis. In the present study, we observed that several colonic inflammatory cytokines (TNF‐α, IL‐1β, IFNg) and Wnt pathway specific genes (e.g. Axin2) were upregulated in an obese state (p < 0.05), whereas the genetic ablation of TNF‐α suppressed the elevation of Wnt‐signaling induced by dietary obesity, as indicated by decreased levels of phopho‐GSK3β, and active β‐Catenin (p < 0.05), two key components in Wnt pathway cascade. A Wnt pathway specific gene expression profiling further demonstrated that the genetic abolishment of TNF‐α attenuated aberrations of several genes within the colonic Wnt pathway cascade including the over‐expressed Axin2, a readout of the Wnt pathway (p < 0.05). Colonic epithelial proliferation (Ki‐67), which is partially under the control of Wnt signaling, was also decreased by the blockade of TNF‐in obese mice (p < 0.05). These results indicate that obesity‐driven inflammation plays a role in the regulation of the tumorigenic Wnt‐signaling pathway, which contributes to the development of obesity‐associated CRC.Support or Funding InformationSupported in part by a USDA/NIFA grant, a USDA/Hatch grant and a HNRCA competitive intramural pilot grant to ZL
Recent decades have seen a rapid increase in obesity, which is associated with increased risk of multiple medical complications including diabetes, cardiovascular disease, and some cancers. As obesity has reached an epidemic level and no decrease is projected in the near future, new prevention and medication strategies are needed for obesity and related disorders. Tumor necrosis factor alpha (TNF‐α), a critical pro‐inflammatory cytokine, is elevated in adipose tissue and its expression level correlates with the degree of obesity. Impressive evidence shows that diets or drugs, which are used to reduce inflammation, can ameliorate obesity. The objective of the study was to investigate the role of TNF‐α in high‐fat diet‐induced obesity and thereby to examine the potential implication of targeting TNF‐α in obesity and obesity‐related complications. Fifty‐two wildtype and 52 TNF‐α knockout mice (male and female evenly) with the same C57BL6 genetic background were randomly divided into two groups receiving either a high‐fat diet (HFD, 60% fat) or a low fat diet (LFD, 10% fat) for 16 weeks. Body weight were monitored weekly and body composition were determined by Magnetic Resonance Imaging (MRI), The expression of pro‐inflammatory cytokines, key components within Wnt pathway and determinants of adipogenesis in the visceral adipose tissue were also measured. The results shows that, while there are no significant differences among the LFD groups (p > 0.05), wildtype HFD group has significantly higher body weight and fat composition compared to TNF‐α knockout HFD group. In addition to TNF‐α itself, the expressions of IL‐6 and IFNγ, as measured by chemiluminescent immunoassay, were also significantly lower in the HFD‐induced obese animals with TNF‐α knockout when comparing to the wildtype HFD group (p < 0.05). In the obese state, the genetic ablation of TNF‐α significantly reduced Wnt‐signaling, as indicated by decreased phospho‐GSK3β and active β‐catenin as well as Wnt pathway downstream genes (p < 0.05). The deletion of TNF‐α significantly increased both mRNA and protein expression of PPARγ and C/EBPα, two critical genes which are key determinants of adipogenesis. All these data collectively indicate that depletion of TNF‐α may ameliorate HFD‐induced obesity, potentially via altering Wnt‐signaling and determinants of adipogenesis.Support or Funding InformationThis project is supported by USDA grants (2014‐67017‐21762 and MAS00454) and the Pilot grant from Rays of Hope Center for Breast Cancer Research
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