Metabolic Endotoxemia Amplifies Estrogen Signaling Through Stromal Crosstalk in Obesity-Associated Breast Cancer

Obesity has been consistently associated with several types of malignant tumors, including hormone-responsive breast carcinoma (BC) in postmenopausal patients. BC is the most diagnosed malignancy and the leading cause of cancer-related morbidity and mortality among women worldwide. The predominant association between obesity and hormone-responsive BC subtypes is often explained by the increased local production of estrogens due to upregulation of aromatase, the rate-limiting enzyme in estrogen biosynthesis, in the chronically inflamed "obese" adipose tissue. However, the underlying molecular mechanisms are not fully defined. One potential mediator of inflammatory responses in the setting of obesity is bacterial endotoxin. Indeed, subclinical concentrations of endotoxin are chronically present in the circulation of obese patients and experimental animals (the phenomenon termed 'metabolic endotoxemia' [ME]). Here, we investigated whether ME conditions are mechanistically involved in augmented estrogen reactivity that sustains the obesity-BC link, focusing primarily on ME effects on key cellular components of the BC microenvironment (i.e., fibroblasts, macrophages). Our findings identify ME as a microenvironmental driver that directly induces aromatase expression in adipose fibroblasts, and simultaneously triggers upregulation of estrogen receptor levels in breast tumor cells via a macrophage-mediated mechanism. This dual action of ME in fueling obesity-accelerated hormone-dependent breast tumorigenesis may suggest new avenues for both therapeutic intervention and prevention of BC-promoting consequences of excess adiposity in an increasingly obese population.