Bisphenol A disruption promotes mammary tumor microenvironment via phenotypic cell polarization and inflammatory response

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Ruiz, Thalles F. R. ; Colleta, Simone J. ; dos Santos, Diego D. ; Castro, Nayara F. C. ; Cabral, Agata S. ; Calmon, Marilia F. ; Rahal, Paula ; Gil, Cristiane D. ; Girol, Ana Paula ; Vilamaior, Patricia S. L. ; Leonel, Ellen C. R. ; Taboga, Sebastiao R.

• Document type: Journal article
• Source: Cell Biology International; v. 47, n. 6, p. 11-pg., 2023-03-11.

Abstract

Inflammation in the established tumor microenvironment (TME) is often associated with a poor prognosis of breast cancer. Bisphenol A (BPA) is an endocrine-disrupting chemical that acts as inflammatory promoter and tumoral facilitator in mammary tissue. Previous studies demonstrated the onset of mammary carcinogenesis at aging when BPA exposure occurred in windows of development/susceptibility. We aim to investigate the inflammatory repercussions of BPA in TME in mammary gland (MG) during neoplastic development in aging. Female Mongolian gerbils were exposed to low (50 mu g/kg) or high BPA (5000 mu g/kg) doses during pregnancy and lactation. They were euthanized at 18 months of age (aging) and the MG were collected for inflammatory markers and histopathological analysis. Contrarily to control MG, BPA induced carcinogenic development mediated by COX-2 and p-STAT3 expression. BPA was also able to promote macrophage and mast cell (MC) polarization in tumoral phenotype, evidenced by pathways for recruitment and activation of these inflammatory cells and tissue invasiveness triggered by tumor necrosis factor-alpha and transforming growth factor-beta 1 (TGF-beta 1). Increase of tumor-associated macrophages, M1 (CD68 + iNOS+) and M2 (CD163+) expressing pro-tumoral mediators and metalloproteases was observed; this aspect greatly contributed to stromal remodeling and invasion of neoplastic cells. In addition, the MC population drastically increased in BPA-exposed MG. Tryptase-positive MCs increased in disrupted MG and expressed TGF-beta 1, contributing to EMT process during carcinogenesis mediated by BPA. BPA exposure interfered in inflammatory response by releasing and enhancing the expression of mediators that contribute to tumor growth and recruitment of inflammatory cells that promote a malignant profile. (AU)

• FAPESP's process: 20/00160-1 - Effects of maternal exposure to bisphenol A on adult and senescent gerbil (Meriones unguiculatus) prostate
• Grantee: Simone Jacovaci Colleta
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/23383-6 - Histopathological repercussions of the endocrine disrupters bisfienol-A and 17-beta-oestradiol on mammary glands and female prostate of the Mongolian Gerbil and their relatioships with the chemically induced carcinogenesis by MNU
• Grantee: Sebastião Roberto Taboga
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/01240-9 - Late effects of bisphenol A exposure in the mammary gland of female gerbils during pregnancy and lactation
• Grantee: Thalles Fernando Rocha Ruiz
• Support Opportunities: Scholarships in Brazil - Master