Obesity is associated with increased risk of breast and other cancers. However, the complexity of the underlying mechanisms, together with the interplay of diet and physical activity-contributing to energy balance-and the role of adipose tissue, pose challenges to our understanding of the basis of this increased risk. Epidemiologic studies have documented a higher obesity prevalence in US black women compared to white women. Elucidation of the contribution of potential biological differences among racially distinct groups to their differences in breast cancer (BC) risk and mortality have been topics of considerable interest in recent years. The racial and ethnic variation in body fat distribution may account for at least part of the differences in breast cancer rates in these populations. Yet, while black women exhibit higher rates of obesity compared to white women, this does not translate directly into higher rates of BC. In fact, overall, BC in black women occurs with a lower incidence than BC in white women. Obesity is a known risk factor for postmenopausal breast cancer, and growing evidence suggests that abdominal obesity, also known as central obesity, may increase risk for triple negative breast cancer, which is more common in premenopausal women. The positive association of postmenopausal BC risk and specifically estrogen receptor (ER)-positive BC, is presumably due largely to accumulation of estrogen in the adipose tissue of the breast and other tissues. Of the two main types of adipose tissue-subcutaneous and visceral-visceral adipocytes are more active metabolically. Such adipose tissue harbors multiple molecular entities that promote carcinogenesis: endocrine molecules/hormones, immunologic factors, inflammatory cytokines, metabolic alterations, and other components of the microenvironment. Expression of these culpable entities is largely regulated by epigenetic mechanisms. The interrelationship between these entities and drivers of epigenetic alteration are critical to the regulation of pathways connecting obesity and cancer risk. Initiatives to counteract the carcinogenic effects of obesity have primarily involved modulation of energy balance by diet. However, targeting of specific molecular abnormalities characterizing adiposity offers an alternative approach to preventing cancer. Our goal in this review is to first discuss the major mechanisms contributing to the obesity-breast cancer link. We will also consider race, specifically black/white differences, as they relate to the association of obesity with breast cancer risk. Then we will enumerate strategies targeting these mechanisms to reduce BC risk, in large part by way of dietary interventions with potential to mitigate the cancer-promoting components of adiposity.

Background/Aims Altered expression of microRNAs is frequently detected during tumor development; however, it has not been established if variations in the expression of specific microRNAs are associated with differences in the susceptibility to tumorigenesis. Methods Inbred male inbred C57BL/6J and DBA/2J mice were fed a lipogenic methyl-deficient diet, which causes liver injury that progresses to liver tumors. Differentially expressed microRNAs were identified by μParaflo microRNA microarray analysis and validated by quantitative reverse transcription PCR. Results We identified 74 significantly up- or down-regulated microRNAs, including miR-29c, miR-34a, miR-122, miR-155, miR-200b, miR-200c, and miR-221, in the livers of mice fed a methyl-deficient diet for 12 weeks as compared to their age-matched control mice. The targets for these microRNAs are known to affect cell proliferation, apoptosis, lipid metabolism, oxidative stress, DNA methylation, and inflammation. Interestingly, DBA/2J mice, which develop more extensive hepatic steatosis-specific pathomorphological changes, had a greater extent of miR-29c, miR-34a, miR-155, and miR-200b expression. Conclusions These results demonstrate that alterations in expression of microRNAs are a prominent event during early stages of liver carcinogenesis induced by methyl deficiency. More importantly, our data link alterations in microRNA expression to the pathogenesis of liver cancer and strongly suggest that differences in the susceptibility to liver carcinogenesis may be determined by the differences in the microRNA expression response.

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