At this year’s American Association for Cancer Research (AACR) annual meeting, held virtually last month, several studies presented sought to tease apart the relationships between obesity, inflammation, metabolic factors, and breast cancer.
Researchers, including BCRF investigators Drs. Andrew Dannenberg and Neil Iyengar, showed that poor metabolic health is a much stronger predictor of breast cancer risk than body mass index (BMI)—an insight that could help researchers create interventions that target metabolic factors to prevent the disease.
The links between obesity and breast cancer
Obesity is a causal risk factor of breast and many other types of cancer, particularly estrogen receptor (ER)–positive breast cancer in postmenopausal women and triple-negative breast cancer (TNBC) in premenopausal women. Although there is strong evidence of a link between breast cancer and obesity, researchers do not yet fully understand why it exists.
Obesity is excess adipose (fat) tissue in the body, currently defined by an elevated BMI. Adipose tissue contributes to the regulation of the body’s energy and, when unchecked, can lead to inflammation and metabolic disorders such as altered hormone production and type 2 diabetes—all effects that are associated with tumor development and progression.
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Inflammation leads to altered hormone production and metabolic disease
Chronic, low-grade inflammation is an underlying cause of breast cancer. Microscopic hallmarks of inflammation called crown-like structures (CLS) are commonly found in the breast adipose tissue of obese and overweight women. At AACR, Dr. Dannenberg presented research conducted with Dr. Iyengar showing that CLS are also seen in about one-third of normal weight women, suggesting that inflammation is a more telling risk factor of breast cancer in postmenopausal women than elevated BMI.
Inflammation also leads to metabolic changes that result in distorted hormone production. One well-known example of this phenomenon is the increased production of aromatase, an enzyme that is important for synthesizing the hormone estrogen. ER-positive breast cancers rely on estrogen to grow, so aromatase inhibitors are a commonly used treatment that block the production of estrogen. Along with increased levels of aromatase, inflammation is associated with many changes in gene expression that increase the levels of other pro-inflammatory biomarkers such as leptin, triglycerides, glucose, and insulin.
Insulin is a critical hormone that regulates metabolism by promoting glucose absorption from the blood into liver, fat, and skeletal muscle cells. Insulin resistance is an attribute of type 2 diabetes, and in those who are diagnosed, the amount of insulin needed to lower their blood glucose and get into cells can be anywhere from three to 10 times higher than normal. Pre-diabetes and insulin resistance are seen in aggressive TNBC biology. Remarkably, the signaling pathways activated in TNBC are already active in pre-cancerous breast tissue, which presents an opportunity to target them to prevent TNBC.
Metabolic health and precision prevention
Biomarkers of metabolic health are proving to be far more important than BMI in terms of increased breast cancer risk. An individual’s body composition is a more accurate measure of increased breast cancer risk than BMI—that is, a normal-weight woman with higher body fat and lower muscle mass could be at higher risk than an overweight woman with lower body fat and higher muscle mass. An upcoming clinical trial will determine whether lifestyle intervention can improve body composition and metabolic biomarkers in postmenopausal women with excess body fat and a normal BMI.
Metformin is a drug that is commonly used to treat type 2 diabetes that works by increasing insulin sensitivity by decreasing glucose production in the liver. An ongoing clinical trial is testing whether metformin can lower the effects of excess insulin and decrease breast cancer incidence in premenopausal women who have abnormal breast cells but have not yet developed breast cancer.
Looking forward
To better predict breast cancer risk, metabolic links to breast cancer can be more deeply probed with metabolomic profiling: uncovering potentially predictive biomarkers that could provide clinicians with a more refined picture of an individual’s metabolic signature that is associated with breast cancer development. In addition, the discovery of novel pathways that involve these metabolites could be targeted to stop breast cancer development.
MORE HIGHLIGHTS FROM AACR 2021:
Potential Treatment Methods to Improve Outcomes for ER-Positive Breast Cancer
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