Paradoxical effects of obesity on pre‑ vs. post‑menopausal breast cancer: The epigenetic mechanisms (Review)

Abstract

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

Systematic Review and Meta-Analysis of the Impact of Bariatric Surgery on Future Cancer Risk

“…When compared to conventional treatment, BMS results in more substantial and durable weight loss while improving inflammatory markers, insulin sensitivity (HOMA-IR) and resolving other underlying disease processes, including metabolic syndrome, T2DM, glycosylated haemoglobin (HbA1c), NASH, aromatase activity, visceral obesity, hypoxia and OSA [ 23 , 31 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ]. RYGB surgery has been shown to decrease macrophage infiltration and crown-like structures (CLS) in subcutaneous adipose tissue (SAT), indicating improvement in local white adipose tissue (WAT) inflammation.…”

“…Obesity results in cross-talks between leptin, ER-α receptor, IGF signalling and the transactivation of EGFR, which is thought to increase the risk of postmenopausal breast cancer. Other studies have suggested obesity decreases the risk of developing premenopausal breast cancer [ 74 , 83 , 110 ]. The influence of the ER status in obesity-related breast cancer was elucidated by Feigelson et al (2020), who found that bariatric surgery significantly reduced the future risk of ER+ postmenopausal breast cancer (HR 0.51, 95% CI, 0.38–0.69, p <0.001) but not ER- postmenopausal breast cancer (HR 0.79, 95% CI, 0.41–1.51, p = 0.47) [ 56 ].…”

“…Conversely, bariatric surgery was protective for the future risk of premenopausal ER- breast cancer (HR 0.37, 95% CI, 0.17–0.81, p = 0.01) but not premenopausal ER+ breast cancer (HR 0.84, 95% CI, 0.63–1.14, p = 0.27) [ 56 ]. The data are influenced by the predominance of ER+/PR+ postmenopausal breast cancer, the relative frequency of ER+ vs. ER- breast cancers and the lack of BMS intervention studies that include the menopausal and ER+/ER- breast cancer status [ 74 , 83 , 109 , 110 ].…”

Molecular Mechanisms of Western Diet-Induced Obesity and Obesity-Related Carcinogenesis—A Narrative Review

“…Obesity results in epigenetic alterations such as DNA methylation, which has been correlated with the future development of CRC and breast cancer [ 145 , 146 , 147 , 148 , 149 ]. The other main types of epigenetic changes include histone modifications and non-coding mRNA interference.…”

“…The other main types of epigenetic changes include histone modifications and non-coding mRNA interference. Histone modifications regulate gene expression through the addition or removal of a chemical group (acetylation, methylation, phosphorylation, ubiquitination) which affects the compaction of chromatin [ 149 ]. As discussed in the section on dysfunctional adipocyte exosomes, microRNAs control gene expression by cleaving mRNA or interfering with the production of proteins by coding RNA [ 145 ].…”