Micro-RNA in weight loss and breast cancer

From the McTiernan Group, Public Health Division

Obesity has been associated with alterations in a variety of risk factors for breast cancer including inflammation-related biomarkers, insulin resistance, biomarkers of angiogenesis, sex steroid hormones, leptin, and oxidative stress. Micro RNA (miRNA) are short non-coding RNAs that help regulate gene expression. Mature miRNAs are released into the bloodstream as exosomes, microvesicles, or bound to lipoproteins. Once in circulation, they remain stable. They can also be transported to near or distant sites in secretory forms to carry out regulatory functions, including altering gene expression.  Few studies have analyzed the effects of weight loss on circulating miRNAs.  The McTiernan Group tested the combined effect of dietary weight loss and exercise on circulating levels of 23 miRNAs that were previously shown to control expression of genes related to high-risk for breast cancer, obesity, and obesity-related processes. The findings of this study were published in Epigenetics.

This current study is ancillary to the Nutrition and Exercise in Women (NEW) randomized controlled trial (RCT) of postmenopausal women aged 50-75 years who had overweight/obesity and low physical activity. The NEW study randomly assigned women to a 12-month reduced-calorie diet program, a moderate to vigorous exercise intervention, both, or control, and tested the effects on circulating biomarkers related to  breast cancer risk. For this ancillary study, participants  in the 2 reduced-calorie diet arms with the highest degree of weight loss were compared to the controls who did not lose weight. The women in the intervention versus control arms were very similar for breast cancer risk factors  such as age, parity, and family history of breast cancer. The ancillary study sample consisted of 36 controls (participants who did not lose weight at 12-months) and 53 participants in the weight loss group (participants who loss >10% of weight at 12-months). Clinic staff collected fasting blood samples at baseline and 12-months following the specified interventions to identify changes in miRNA levels.  Generalized estimating equations modification of linear regression were utilized to measure the  effects of weight loss on miRNA levels.

The authors found that participants in the weight loss groups had greater reductions in miR-122 (involved in regulation of breast cancer development, adipogenesis, inflammation, an angiogenesis) and those with the highest degree of weight loss had the greatest reductions in miR-122 compared to controls.  After adjusting these data for covariates, there was a significant correlation between body mass index (BMI) and miR-122.  The McTiernan Group summarized the results, “In epidemiological studies, elevated circulating levels of these hormones are associated with increased risk of breast cancer in postmenopausal, overweight/obese women; weight reduction is associated with reduced risk of breast cancer. A possible mechanism is reduction of adipose tissue, in turn reducing extra-ovarian production of sex steroid hormones in adipose tissue. Linking changes in miRNA expression with weight loss, may have downstream impacts on expression of specific genes involved in these processes.  Similarly, we investigated miRNAs associated with regulation of inflammation, another process that is associated with increased risk of breast cancer, and that is reduced with weight loss.”

Based on the study’s results, the McTiernan’s Group hypothesis was supported: women who lost weight saw the greatest changes in miR-22 levels.  The McTiernan Group concluded that future studies should consist of larger sample sizes and investigate the physiological mechanisms between obesity and cancer risk.  

Graphical Representation of Change from baseline to 12 months in normalized miRNAs
Change from baseline to 12 months in normalized miRNAs Image from Dr. Catherine Duggan

This research was supported by the National Cancer Institute and the Breast Cancer Research Foundation.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members John Scheel, Ching-Yun Wang, Anne McTiernan contributed to this work.

Duggan C, Tapsoba JD, Scheel J, Wang CY, McTiernan A. 2022. Weight loss reduces circulating micro-RNA related to obesity and breast cancer in postmenopausal women. Epigenetics. 1-4