Abstract
Epidemiologic evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase plays an important role in energy homeostasis and inhibits the actions of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the cyclic AMP-responsive element binding protein-dependent regulation of aromatase is a determinant of breast tumor formation through local production of estrogens. The present work aimed to examine the effect of adipokines on aromatase expression and identify additional mechanisms by which prostaglandin E(2) causes increased aromatase expression in human breast adipose stromal cells. Treatment of human adipose stromal cells with forskolin and phorbol 12-myristate 13-acetate (PMA), to mimic prostaglandin E(2), resulted in nuclear translocation of CRTC2. Aromatase promoter II (PII) activity assays showed that CRTC2 in addition to forskolin/PMA treatment significantly increased PII-induced activity. CRTC2 binding to PII was examined by chromatin immunoprecipitation, and forskolin/PMA treatment was associated with increased binding to PII. Treatment of human adipose stromal cells with leptin significantly up-regulated aromatase expression associated with nuclear translocation of CRTC2 and increased binding of CRTC2 to PII. Adiponectin treatment significantly decreased forskolin/PMA-stimulated aromatase expression, consistent with the decreased nuclear translocation of CRTC2 and the decreased binding of CRTC2 to PII. The expression and activity of the AMP-activated protein kinase LKB1 was examined and found to be significantly decreased following either forskolin/PMA or leptin treatment. In contrast, adiponectin significantly increased LKB1 expression and activity. In conclusion, the regulation of aromatase by CRTC2, in response to the altered hormonal milieu associated with menopause and obesity, provides a critical link between obesity and breast cancer.
Highlights
There is substantial epidemiologic evidence to support the conclusion that obesity is linked to the increased risk of several forms of cancer such as colon and breast cancer [1]
The role of CRTC2 in promoter II (PII)-driven aromatase expression was examined in primary human adipose stromal cells treated with 25 Amol/L forskolin and 4 nmol/L phorbol 12-myristate 13-acetate (PMA) to mimic the effects of prostaglandin E2 (PGE2)
Mutation of the proximal cyclic AMP-responsive elements (CRE) completely abolished the CRTC2-mediated activation of PII (Fig. 1B, www.aacrjournals.org white columns) compared with the effect observed with cotransfection of CRTC2 with wild-type PII and forskolin/PMA treatment
Summary
There is substantial epidemiologic evidence to support the conclusion that obesity is linked to the increased risk of several forms of cancer such as colon and breast cancer [1]. We believe that inflammatory factors such as prostaglandin E2 (PGE2) produced by the tumorous epithelium activate aromatase expression in breast adipose stromal cells (the cell type in adipose tissue where aromatase is expressed) via the E prostanoid 2 receptor, which results in stimulation of adenylyl cyclase, and the E prostanoid 1 receptor, which stimulates diacylglycerol and inositol triphosphate formation [6]. This is an example of the role of epithelial/mesenchymal interactions in carcinogenesis. These stimulatory pathways work in concert to facilitate tumor-driven aromatase expression in the breast [8]
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