Blood biomarkers reflect the effects of obesity and inflammation on the human breast transcriptome

Abstract

Obesity is a risk factor for the development of post-menopausal breast cancer. Breast white adipose tissue (WAT) inflammation, which is commonly found in women with excess body fat, is also associated with increased breast cancer risk. Both local and systemic effects are likely to be important for explaining the link between excess body fat, adipose inflammation and breast cancer. The first goal of this cross-sectional study of 196 women was to carry out transcriptome profiling to define the molecular changes that occur in the breast related to excess body fat and WAT inflammation. A second objective was to determine if commonly measured blood biomarkers of risk and prognosis reflect molecular changes in the breast. Breast WAT inflammation was assessed by immunohistochemistry. Bulk RNA-sequencing was carried out to assess gene expression in non-tumorous breast. Obesity and WAT inflammation were associated with a large number of differentially expressed genes and changes in multiple pathways linked to the development and progression of breast cancer. Altered pathways included inflammatory response, complement, KRAS signaling, TNFα signaling via NFкB, IL6-JAK-STAT3 signaling, epithelial mesenchymal transition, angiogenesis, interferon γ response, and TGF-β signaling. Increased expression of several drug targets such as aromatase, TGF-β1, IDO-1 and PD-1 were observed. Levels of various blood biomarkers including hsCRP, IL6, leptin, adiponectin, triglycerides, HDL cholesterol and insulin were altered and correlated with molecular changes in the breast. Collectively, this study helps to explain both the link between obesity and breast cancer and the utility of blood biomarkers for determining risk and prognosis.

Translating energy balance research from the bench to the clinic to the community: Parallel animal‐human studies in cancer

“…59 BWATi is associated with an increased risk of breast cancer in women with a history of benign breast disease 60 and increased levels of aromatase, the rate-limiting enzyme for converting androgens to estrogens. 56,61 An increased ratio of select estrogens to androgens has been observed in association with crown-like structures in breast adipose tissue and serum in patients with breast cancer. 62 Elevation of estrogens is believed to have a paracrine effect on breast epithelial cells, resulting in an increased risk of hormone receptor-positive breast cancer.…”

“…An RNAsequencing analysis showed that BWATi was associated with numerous transcriptome changes, including elevated levels of aromatase. 61 Moreover, the relationship between excess body fat in postmenopausal women with normal BMI and breast cancer risk was determined using data from the Women's Health Initiative. 63 In 3460 postmenopausal women with normal BMI, the risk of breast cancer was compared in those with high versus low body fat (measured by dual-energy absorptiometry scan).…”

“…The potential importance of excess body fat and BWATi in the development of breast cancer in postmenopausal women with normal BMI was evaluated. An RNA‐sequencing analysis showed that BWATi was associated with numerous transcriptome changes, including elevated levels of aromatase 61 . Moreover, the relationship between excess body fat in postmenopausal women with normal BMI and breast cancer risk was determined using data from the Women's Health Initiative 63 .…”