Research

Overview

Obesity is a leading modifiable risk factor for at least 13 types of cancer, including hormone receptor-positive breast cancer after menopause. Several local and systemic changes are hypothesized to support this relationship, including increased circulating levels of insulin and glucose, as well as adipose tissue-derived estrogens, adipokines and inflammatory mediators. Metabolic pathways of energy production and utilization are dysregulated in tumor cells and this dysregulation is a newly accepted hallmark of cancer. Dr Brown's team has driven groundbreaking work to understand the role of metabolic pathways in the breast microenvironment and in regulating aromatase, the enzyme responsible for the production of estrogens, in driving breast cancer risk in obesity. Based on these discoveries, they identified the AMPK-activating anti-diabetic drug metformin as a tissue selective inhibitor of estrogen production.

Through these studies, an appetite-regulating hormone was identified as a potential new breast cancer therapeutic. Ghrelin and its unacylated form, des-acyl ghrelin, are produced predominantly by the gut and circulating levels are inversely associated with obesity. They found that ghrelin and des-acyl ghrelin potently inhibit aromatase and estrogen production in breast adipose tissue, not only providing an additional mechanism for the obesity-associated increase in aromatase, but also leading to the hypothesis that des-acyl ghrelin analogues may be of therapeutic relevance. The team's work has also explored the effects of des-acyl ghrelin on tumor growth. Effects appear to be tumor-type specific and dependent on interaction with the extracellular matrix.

Following on from this work, the impact of obesity and breast adipose-derived factors on breast tumorigenesis was explored. The lab was particularly interested in understanding whether poor metabolic health may contribute to breast cancer penetrance in BRCA mutation carriers. These women have an elevated risk of developing breast and ovarian cancer, yet little is known as to whether modifiable risk factors contribute to tumor formation. In NIH-funded work, body mass index (BMI) and markers of metabolic dysfunction were found to be positively correlated with more DNA damage in the non-cancerous breast epithelium of BRCA mutation carriers. Data in high fat diet-fed Brca1-/+ mice support a role for obesity in driving DNA damage in the normal mammary gland. Mechanistic studies have demonstrated that the estrogen receptor degrader fulvestrant or anti-diabetic drug metformin can reduce DNA damage in human tissue, suggesting potential opportunities for intervention. Using a carcinogen-induced Brca1 -/+ model developed in the Brown lab, high fat feeding was found to lead to increased tumor penetrance.

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