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A Potential Pathogenic Mechanism Linking Obesity, Breast Cancer and Estrogen Receptor Expression

David Pisani, Etienne Mark Paris, Gordon Caruana Dingli.

Abstract
Obesity is a growing problem in the Western world and has been strongly linked to post-menopausal breast cancer. After menopause, adipose tissue assumes a major role in estrogen production, primarily because it expresses aromatase, which is critical in estrogen synthesis. Obese women have higher levels of circulating estrogen and lower levels of sex hormone-binding globulin. Free estrogen can promote fat deposition in the breast, which further increases local breast estrogen production. Estrogen promotes ductal proliferation by interacting with intracellular receptors, especially ER-a, but also through a host of membrane receptors like GPR30, which terminate on cyclin D1 activation, amongst other signals. Supplemental estrogen for this process can be provided by local macrophages and stromal cells. Excessive ductal proliferation is associated with accumulation of mutations in various genes, including HER2/neu, DIRAS3, TP53 and ESR1, which promote aberrant cell proliferation. This process is aided by genotoxic estrogen metabolites and by increased enterohepatic circulation of estrogen byproducts. In addition, hyperestrogenemia inhibits ubiquitin-mediated receptor degradation, hence promoting estrogen receptor expression in tumour cell lines. Other adipocytokines, like leptin, interleukin-6, adiponectin and insulin, have also been linked to breast cancer, with several molecular cross-interactions with estrogen receptor signaling pathways.

Key words: Adipose Estrogen Adipocytokine Breast Cancer Estrogen Receptor



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