Identification of molecular and cellular pathways mediated by estrogen receptors involved in castration-resistant Prostate Cancer: studies with cell lines and spheroids

• Grant number: 23/13622-1
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Carolina Meloni Vicente
• Grantee: Carolina Meloni Vicente
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Catarina Segreti Porto ; Gustavo José da Silva Pereira ; Leny Toma ; Miriam Galvonas Jasiulionis

Abstract

Castration-resistant prostate cancer (CRPC) is characterized by poor prognosis and a median survival ranging from 10 to 20 months. Few therapeutic targets have been identified in CRPC, and further studies are needed to unravel the complex mechanism underlying tumor resistance and spread. Circulating 17²-estradiol levels are elevated as men age, impacting the prostate. Furthermore, estrogens can be produced locally within the prostate via conversion of testosterone to 17²-estradiol by aromatase expressed in the prostate stroma. Using Immunohistochemistry, studies have revealed the presence of both estrogen receptors, ESR1 (ER±) and ESR2 (ER²), in prostate cancer samples obtained from patients, although their relative levels at different stages of cancer remain unknown. Previous studies from our laboratory, carried out in monolayer cell cultures, demonstrated the importance of estrogen and its receptors in human immortalized CRPC cell lines, acting on cell proliferation and on cancer-related signaling pathways. However, the interaction between EGFR and ERs in prostate cancer has not yet been described. Furthermore, it is known that three dimensions cellular systems (3D), such as cellular spheroids, make cell-cell and cell-extracellular matrix interactions more physiologically relevant, providing more accurate preclinical models. Thus, we believe that the elaboration of spheroids with CRPC cell lines represents an important model for the study of estrogen and its receptors in this type of tumor. Therefore, this project aims to analyze the coordinated action between EGFR and ERs in CRPC cultures in monolayers. In addition, to study the expression of estrogen receptors in CRPC spheroids and their functions in these models. (AU)