Obesity Is Associated with Inflammation and Elevated Aromatase Expression in the Mouse Mammary Gland

Abstract

Elevated circulating estrogen levels are associated with increased risk of breast cancer in obese postmenopausal women. Following menopause, the biosynthesis of estrogens through CYP19 (aromatase)-mediated metabolism of androgen precursors occurs primarily in adipose tissue, and the resulting estrogens are then secreted into the systemic circulation. The potential links between obesity, inflammation, and aromatase expression are unknown. In both dietary and genetic models of obesity, we observed necrotic adipocytes surrounded by macrophages forming crown-like structures (CLS) in the mammary glands and visceral fat. The presence of CLS was associated with activation of NF-kB and increased levels of proinflammatory mediators (TNF-a, IL-1b, Cox-2), which were paralleled by elevated levels of aromatase expression and activity in the mammary gland and visceral fat of obese mice. Analyses of the stromalvascular and adipocyte fractions of the mammary gland suggested that macrophage-derived proinflammatory mediators induced aromatase and estrogen-dependent gene expression (PR, pS2) in adipocytes. Saturated fatty acids, which have been linked to obesity-related inflammation, stimulated NF-kB activity in macrophages leading to increased levels of TNF-a, IL-1b, and Cox-2, each of which contributed to the induction of aromatase in preadipocytes. The discovery of the obesity ! inflammation ! aromatase axis in the mammary gland and visceral fat and its association with CLS may provide insight into mechanisms underlying the increased risk of hormone receptor-positive breast cancer in obese postmenopausal women, the reduced efficacy of aromatase inhibitors in the treatment of breast cancer in these women, and their generally worse outcomes. The presence of CLS may be a biomarker of increased breast cancer risk or poor prognosis.

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

“…The resulting cDNA was then used for amplification. The primers for murine and human aromatase have been described previously (5,9,44,45). The primers for PKM2 were 5Ј-GTCTGGAGAAACAGCCAAGG-3Ј (forward) and 5Ј-CGGAGTTCCTCGAATAGCTG-3Ј (reverse) (46).…”

“…3 H]androstenedione (5,9,18,44,45). The reaction was also done in the presence of letrozole, a specific aromatase inhibitor, as well as a specificity control and without NADPH as a background control.…”

High-Density Lipoprotein-Cholesterol, Daily Estradiol and Progesterone, and Mammographic Density Phenotypes in Premenopausal Women

“…Low HDL-C and sex hormone levels may, in combination, stimulate growth of epithelial and stromal tissues, influencing both absolute and percent mammographic density. Low levels of HDL-C have been observed to induce higher levels of proinflammatory cytokines (6), and proinflammatory cytokines were recently found to induce higher local estradiol levels and cellular proliferation in the breast (44,45), and to be associatied with percent mammographic density (46). Furthermore, hypercholesterolemia, strongly associated with low HDL-C, may induce angiogenesis (47), and accelerating breast cell growth and metastasis (8,9).…”

“…Thus, the breast tissue may experience higher levels of circulating cholesterol (8, 9), Table 4. The associations between salivary and serum estradiol (SD) and progesterone (SD) and percent mammographic density (%), stratified by tertiles of HDL-C HDL-C <1.39 increased low-grade inflammation (44), and higher levels of total endogenous estradiol and estradiol locally produced in the breast (44,45). Moreover, immune cells and cytokines may interact in a paracrine manner with ovarian steroids in mammary cells (48), and support the present observation, and the hypothesis that mediators of inflammatory cellular cascades, such as low HDL-C, may influence mammographic density phenotypes (12).…”

IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression

“…Characteristics of EMT, an orchestrated program in which cell-cell and cell-extracellular matrix interactions are altered to enhance tumor progression and initiate local invasion and metastasis (Thiery 2003), include the progressive loss of epithelial markers, such as E-cadherin, and gain of mesenchymal markers, such as snail, slug, vimentin, N-cadherin, twist, transforming growth factor B1 (Tgfb1), and matrix metalloproteinases (Mmps) (Rucklidge et al 1994). Increased body adiposity (Calabro & Yeh 2007, Subbaramaiah et al 2011 and tumoral Akt activation (Balkwill 1998, 2004, Roca et al 2008 are also associated with increased tumoral chemokine expression. Chemokines, whichare a subfamily of secreted cytokines from adipocytes, macrophages, and other cells that stimulate directed chemotaxis in nearby responsive cells, increase inflammation, tumor progression, and invasion in multiple tumor types (Balkwill 2004, Kulbe et al 2004, Szlosarek & Balkwill 2004.…”