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Effects of melatonin and 17beta-estradiol on the expression profile of microRNAs and their targets in invasive ductal carcinoma of the breast

Grant number: 22/04174-2
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): August 01, 2023
Effective date (End): July 31, 2025
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal Investigator:Edmund Chada Baracat
Grantee:Bruna Cristine de Almeida
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/24224-9 - Extra reproductive effects of melatonin on the genital system and breast, AP.TEM

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that act in gene expression regulation. Abnormal expression is associated with cellular transformation, compromised therapeutic response, and worse prognosis in breast carcinoma due to regulatory effects on important signaling pathways. Nowadays, there is great interest in identifying modulating substances of miRNA expressions that might be used for targeted therapy in several diseases. In this context, melatonin has been described as a miRNAs regulator, inhibiting the risk of cellular malignancy.Additionally, it is known that an imbalance in estrogen signaling (E2) is often associated with the onset of breast cancer. Thus, the present study aims: 1) to identify differentially expressed miRNAs in invasive ductal carcinoma (IDC) cell lines stimulated or not by E2 and treated with melatonin; 2) to identify the main target genes with differential regulation in treated cells; 3) functionally validate in vitro and in vivo, the role of miRNAs involved in E2 regulation after the treatment with melatonin by genetic manipulation. The IDC cells: T47D, MCF7 (luminal A types), and MDA-MB-231 (triple-negative type) will be stimulated with E2 and submitted to treatment with melatonin; the cells of the control group will be grown only in culture media. miRNAs expression profile and target genes will be evaluated using the qRT-PCR array analysis platforms. The functional validation step will be used siRNAs (silencing) or mimics (induction) systems, which depend on the expression profile of the interested molecule. The effect of treatments and genetic manipulation on the cells' phenotype will be assessed by cellular proliferation, migration, and invasion assays. Based on the results obtained, a target gene will be selected for in vivo validation, by the CRISPR-Cas9 system. This step will be carried out at the University of Michigan (Ann Arbor), under Prof. Dr. Carol Elias's supervision. This project's innovative proposal is to evaluate the genetic and epigenetic effects of the melatonin treatment after cell induction with E2 in IDC. This solicitation is a part of the Thematic Project (2018/24224-9) funded by this promotion agency and its results will bring contributions to biological knowledge and the clinical management of these tumors.

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