Cancer Letters: COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice (Bishop)

Rosângela MayerGonçalvesa, Marina Delgoboa, Jonathan Paulo Agnesa, Raquel Nascimento das Nevesa, MarceloFalchettia, Tuany Casagrandea, Ana Paula Vargas Garciab, Thaynan Cunha Vieirab, Nauana Somensic, Maciel Alencar Bruxeld, Daniel Augusto Gasparin Bueno Mendese, Alex Rafachod, André Báficae, Daniel Pens, Gelainc, José Cláudio Fonseca, Moreirac, Geovanni Dantas Cassalib, Alexander James Roy Bishopf, AlfeuZanotto-Filhoa

Abstract

Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production has been correlated with inflammation and local estrogen biosynthesis via aromatase. Using a mouse model of 7,12-dimethylbenz[a]anthracene/medroxyprogesterone-acetate (DMBA/MPA)-induced carcinogenesis, we demonstrated that an obesogenic diet promotes mammary tissue inflammation and local estrogen production, and accelerates mammary tumor formation in a COX-2-dependent manner. High-sugar/fat (HSF) diet augmented the levels of the pro-inflammatory mediators MCP-1, IL-6, COX-2, and PGE2 in mammary tissue, and this was accompanied by crown-like structures of the breast (CLS-B) formation and aromatase/estrogen upregulation. Treatment with a COX-2 selective inhibitor, etoricoxib, decreased PGE2, IL-6, MCP-1, and CLS-B formation, as well as reduced aromatase protein and estrogen levels in the mammary tissue of mice, fed an HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to the HSF diet alone. Inhibition of tumor angiogenesis also seemed to account for the prolonged survival of COX-2 inhibitor-treated animals. In conclusion, obesogenic diet-induced COX-2 is sufficient to trigger inflammation, local estrogen biosynthesis, and mammary tumorigenesis.

Article Categories: Research Paper