Transcription factor-mediated gene regulation of chromosome 1q in breast cancer

Breast cancer is the most commonly diagnosed cancer among women and the fifth cause of cancer deaths in the world. Approximately 80% of breast cancer patients are estrogen receptor alpha (ERα) positive, which is a sequence-specific transcription factor that interacts with DNA either directly by estrogen response elements (EREs) or recruited by other transcription factors (TFs). Forkhead Box A1 (FOXA1) and GATA Binding Protein 3 (GATA3) are two of the major factors that regulate ERα binding and their abnormal expression is associated specifically with luminal A subtype breast cancer. Copy Number Variation (CNV) is a structural variant in the human genome, and chromosome 1 is shown to be one of the most altered regions of breast cancer cells. Consequently, more than 70% of breast tumors display copy number gain in the 1q arm. In this study, the aim is to investigate the association of ERα-GATA3-FOXA1 cistrome with copy number amplifications of chromosome 1q and, finally, gene regulation. For this purpose, chromatin immunoprecipitation followed by sequencing (ChIP-seq) focused analysis of ERα, FOXA1, and GATA3 binding sites, RNA-seq data for the gene expression in MCF7, T47D, and ZR75-1 cell lines, and copy number data collected from Cancer Cell Line Encyclopedia are used. After obtaining the direct and indirect binding sites of targeted TFs, along with the overlapping binding sites among the cell lines, chromosome 1q cytobands with distinguished binding patterns are determined. Custom-made CRISPR/Cas9 libraries are generated in order to target those genomic regions in distinct ways. ChIP-seq and RNA-seq data association focused on specific cytobands revealed upregulated genes that might be promising candidates for further studies.