1. COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice
- Author
-
Thaynan Cunha Vieira, Alex Rafacho, Geovanni Dantas Cassali, José Cláudio Fonseca Moreira, Daniel Augusto Gasparin Bueno Mendes, Ana Paula Vargas Garcia, Maciel Alencar Bruxel, André Báfica, Marcelo Falchetti, Daniel Pens Gelain, Alexander J.R. Bishop, Raquel Nascimento das Neves, Rosângela Mayer Gonçalves, Jonathan Paulo Agnes, Alfeu Zanotto-Filho, Marina Delgobo, Nauana Somensi, and Tuany Casagrande
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,9,10-Dimethyl-1,2-benzanthracene ,DMBA ,Adipose tissue ,Inflammation ,Breast Neoplasms ,Medroxyprogesterone Acetate ,medicine.disease_cause ,Diet, High-Fat ,Dinoprostone ,03 medical and health sciences ,Etoricoxib ,Mice ,0302 clinical medicine ,Aromatase ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Prostaglandin E2 ,Chemokine CCL2 ,Mammary tumor ,biology ,business.industry ,Interleukin-6 ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Oncology ,Estrogen ,Cyclooxygenase 2 ,030220 oncology & carcinogenesis ,biology.protein ,MCF-7 Cells ,Female ,medicine.symptom ,Carcinogenesis ,business ,Sugars ,medicine.drug - 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 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 a HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to 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.
- Published
- 2020