Funder: Alexander von Humboldt Foundation, German Ministry of Education and Research Foreign Office and German Federal

Partner: Dr. Clarissa Gerhäuser, German Cancer Research Center (DKFZ), Heidelberg, Germany

Period: 2023-2025

Leader in Serbia: Dr. Melita Vidaković, Department of Molecular biology IBISS

Other members in Serbia:

Ana Sarić

Dr. Anja Tolić

Abstract

The therapeutic potential towards the triple-negative breast cancers (TNBCs) with the “BRCAness” phenotype is uncovered and started to be of great importance as diagnostic tool. BRCAness refers to malignancies not arisen from germline BRCA1 or BRCA2 but from somatic mutation in either BRCA1 or BRCA2, promoter hypermethylation of BRCA1, or mutations in other genes involved in DNA double stranded break repair.

This project will address the potential use of epigenetic editing tool for BRCAness phenotype induction as a pre-therapeutic approach in TNBCs with unknown mutational signature of BRCA1. Our main objective is to induce BRCAness by suppressing BRCA1 gene expression in TNBC cells via targeted DNA methylation of the BRCA1 promoter using the synthetic epigenetic editing tool (Epi-CRISPR/dCas9/KRAB/DNMT3a3l). The proposed project will examine for the first time, the interconnection of a BRCA1 promoter methylation state (EPIC array) with different active (H3K4) or repressive (H3K9 and H3K27) histone methylation marks, as well as the regulatory role of histone H1 in connecting the two methylation systems, in TNBC cell line using ACT-seq.

Using BRCA1 methylation (BRCAness) as a predictor for therapeutic response to PARPi and other therapeutics, will allow direct TNBC treatment without previous screening for BRCA1 mutations. This methodological setup will facilitate the faster decision toward the use of newest medicaments to increase cells’ susceptibility to apoptosis and cancer cell diminishment.