Biological and clinical significance of flap endonuclease‑1 in triple‑negative breast cancer: Support of metastasis and a poor prognosis

Abstract

Flap endonuclease-1 (FEN1), a structure-specific nuclease participating in DNA replication and repair processes, has been confirmed to promote the proliferation and drug resistance of tumor cells. However, the biological functions of FEN1 in cancer cell migration and invasion have not been defined. In the present study, using online database analysis and immunohistochemistry of the specimens, it was found that FEN1 expression was associated with a highly invasive triple-negative breast cancer (TNBC) subtype in both breast cancer samples from the Oncomine database and from patients recruited into the study. Furthermore, FEN1 was an important biomarker of lymph node metastasis and poor prognosis in patients with TNBC. FEN1 promoted migration of TNBC cell lines and FEN1 knockdown reduced the number of spontaneous lung metastasis in vivo . Ingenuity Pathway Analysis of FEN1-related transcripts in 198 patients with TNBC demonstrated that the polo-like kinase family may be the downstream target of FEN1. PLK4 was further identified as a critical target of FEN1 mediating TNBC cell migration, by regulating actin cytoskeleton rearrangement. The results of the present study validate FEN1 as a therapeutic target in patients with TNBC and revealed a new role for FEN1 in regulating TNBC invasion and metastasis.

Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy

“…Dozens of inhibitors targeting FEN1 through high-throughput screening were filtered, which had more or less of an effect on the treatment of cancer [73]. FEN1 inhibitorbased four chemical structure N-hydroxy urea compounds (Compound #2, Compound #8, Compound #16 and Compound #20) had significant effects on several tumor models, according to previous reports [58,73]. In particular, Compound #8 significantly slowed tumor growth in mice inoculated with HCT116 and HCC1806 cells.…”

“…By analyzing clinical data, it was found that FEN1 protein expression is related to the aggressiveness of epithelial ovarian and breast cancer and the prognosis of patients, and high expression of FEN1 is positively correlated with the survival rate of patients [ 56 ]. Therefore, FEN1 may serve as a key biomarker for ovarian and breast cancer [ 57 , 58 , 59 ]. When FEN1 is abnormally mutated, the expression or function of FEN1 is altered, which may lead to the malignant transformation of normal cells or increase the susceptibility of patients to other carcinogens or the environment [ 60 ].…”

Identification of Flap Endonuclease 1 With Diagnostic and Prognostic Value in Breast Cancer

“…Xu et al. reported that FEN1 promoted the migration and invasion of triple−negative breast cancer (TNBC) cells by modulating the expression level of polo−like kinase 4 (PLK4) ( 35 ). These results indicate that FEN1 is an important regulator of BC progression and a potential target for BC treatment.…”

Curcumin as an Enhancer of Therapeutic Efficiency of Chemotherapy Drugs in Breast Cancer

“…FEN1 overexpression has been confirmed to promote rapid proliferation and CIS drug resistance of breast cancer cells. It is also a significant biomarker of lymph node metastasis and poor prognosis in TNBC patients [132][133][134]. It was shown that the combination of CUR with CIS enhanced the sensitivity of MCF-7, MDA-MB-231, and CIS-resistant MCF-7 (MCF-7/DDP) cells to CIS through downregulation of FEN1 and increased apoptosis in treated cells.…”