Abstract
FANCA is one of the 22 known Fanconi anemia (FA) pathway genes and is indispensable for interstrand crosslink (ICL) repair. It is reported that FANCA is responsible for about 64% of FA cases and one important clinical characterization of FA patients is predisposition to cancer. However, analysis of TCGA database reveals that FANCA level is elevated in breast cancer patients, especially in ER- breast cancer, which is associated with the methylation status at the S-shore of CpG island ahead of FANCA gene. Moreover, the FANCA level is negatively correlated with the survival rate of breast cancer patients. To understand the implication of FANCA in breast cancer development, we have targeted FANCA by either CRISPR mediated knock-out (KO) or shRNA mediated knockdown (KD) in MDA-MB-231 breast cancer cells. Our data suggest that depletion of FANCA protein inhibits breast cancer growth both in vitro and in vivo. On the other hand, overexpressing FANCA in low-FANCA breast cancer cell line MDA-MB-468 promotes cancer cell proliferation. Cell cycle profiling reveals an inefficiency of MDA-MB-231 FANCA KO cells in G1 to S transition due to p21 and p27 upregulation in FANCA KO cells. In addition, the proliferation inefficiency in MDA-MB-231 FANCA KO cells is caused by Rb hypophosphorylation. Therefore, we conclude that FANCA contributes to the breast cancer development by promoting cell cycle progression through Rb/E2F signaling pathway. Our immunoprecipitation (IP) results indicate that in MDA-MB-231, FANCA is interacting with HES1, which is a transcription suppressor that binds to the promoter region of CDKN1A and CDKN1B to promote cell cycle progression, explaining how FANCA participates in cell cycle progression in breast cancer.
Citation Format: Liang Luo, Wenjun Liu, Anna Palovcak, Fenghua Yuan, Fang Li, Daniel Calkins, Yan Li, Karoline Briegel, Daniel Bilbao, Evan Roberts, Christian Mason, Zhao-Jun Liu, Sylvia Daunert, Yanbin Zhang. Defining the role of FANCA in breast cancer development and cell cycle progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3983.