Study of Core Molecular Network Function in Critical Transition of Breast Cancer by the depletion of BRCA1

Abstract

Breast cancer is the most common cancer among women worldwide, and particularly, in cases where individuals inherit mutations associated with high-risk hereditary breast cancer, the likelihood of being diagnosed with breast cancer is known to increase by over 70%. For individuals within this high-risk group with genetic predispositions, apart from preventive mastectomies or regular screenings, there are currently no highly effective methods available to prevent the occurrence of cancer. In this paper, genes that play an important role in transition state changes in breast cancer tumurigenesis are selected,and determine how these genes affect the growth and development of breast cancer caused by BRCA1 depletion. For this purpose, we used the Crispr-Cas9 system to target 2 copies of BRCA1 and designed a mutant cell line in which BRCA1 was knocked out. In this cell line, we used the Tet-On inducible system to identify the estimated transition state time point and candidates acting at this time and confirmed their functions. After knock out BRCA1 and P53, BRCA1 expression decreased until 50 days, but then increased again. And it was confirmed that BRCA1 remained reduced even up to 110 days. In addition, as shown in the results analyzed from public data, we found that SMC2, XCL1, and FOS genes were transiently increased in the designed BRCA1 K.O cell line. It was confirmed that when SMC2 and XCL1 were knocked down at each expected transition state time point, cell proliferation was reduced by 50%. It suggested that XCL1 and SMC2 genes may act as promoters of gene proliferation, and it can be predicted that this increases when BRCA1 depletion occurs. However, the exact transition state point must be found and additional functional studies are needed. Through these results, we would like to molecularly identify transition state changes during the tumorigenesis with BRCA1 mutations in the high-risk group of hereditary cancer and propose preventive methods through this.