COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice

Rosângela Mayer Gonçalves, Marina Delgobo, Jonathan Paulo Agnes, Raquel Nascimento das Neves, Marcelo Falchetti, Tuany Casagrande, Ana Paula Vargas Garcia, Thaynan Cunha Vieira, Nauana Somensi, Maciel Alencar Bruxel, Daniel Augusto Gasparin Bueno Mendes, Alex Rafacho, André Báfica, Daniel Pens Gelain, José Cláudio Fonseca Moreira, Geovanni Dantas Cassali, Alexander James Roy Bishop, Alfeu Zanotto-Filho

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)44-57
Number of pages14
JournalCancer Letters
Volume502
DOIs
StatePublished - Apr 1 2021

Keywords

  • Aromatase
  • Crown-like structures
  • Cyclooxygenase-2
  • Cytokines
  • Prostaglandin E2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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