The prognostic significance of Flap Endonuclease 1 (FEN1) in breast ductal carcinoma in situ

Abstract

Background Impaired DNA repair mechanism is one of the cancer hallmarks. Flap Endonuclease 1 (FEN1) is essential for genomic integrity. FEN1 has key roles during base excision repair (BER) and replication. We hypothesised a role for FEN1 in breast cancer pathogenesis. This study aims to assess the role of FEN1 in breast ductal carcinoma in situ (DCIS). Methods Expression of FEN1 protein was evaluated in a large (n = 1015) well-characterised cohort of DCIS, comprising pure (n = 776) and mixed (DCIS coexists with invasive breast cancer (IBC); n = 239) using immunohistochemistry (IHC). Results FEN1 high expression in DCIS was associated with aggressive and high-risk features including higher nuclear grade, larger tumour size, comedo type necrosis, hormonal receptors negativity, higher proliferation index and triple-negative phenotype. DCIS coexisting with invasive BC showed higher FEN1 nuclear expression compared to normal breast tissue and pure DCIS but revealed significantly lower expression when compared to the invasive component. However, FEN1 protein expression in DCIS was not an independent predictor of local recurrence-free interval. Conclusion High FEN1 expression is linked to features of aggressive tumour behaviour and may play a role in the direct progression of DCIS to invasive disease. Further studies are warranted to evaluate its mechanistic roles in DCIS progression and prognosis.

Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy

“…FEN1 inactivated the P53 signaling pathway by recruiting ubiquitin specific protease 7 (USP7) to prevent the ubiquitination and degradation of murine double minute 2 (MDM2). Further analysis of clinical samples also found that high expression of FEN1 was associated with aggressive tumor behavior and may directly play a role in the progression of carcinoma in situ to aggressive disease [ 63 ]. TGF-β 1 was found to promote epithelial mesenchymal transformation (EMT) phenotype through the up-regulation of FEN1 and down-regulation of MiR-140-5p, leading to the metastasis of HCC cells [ 64 ].…”

Label-Free and Homogeneous Electrochemical Biosensor for Flap Endonuclease 1 Based on the Target-Triggered Difference in Electrostatic Interaction between Molecular Indicators and Electrode Surface

“…Flap endonuclease 1 (FEN1) exhibits multiple values in the early diagnosis [ 1 , 2 ], targeting therapy [ 3 , 4 , 5 , 6 ], and prognostic monitoring [ 7 , 8 ] of various cancers. Traditional assays, including western blot, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA) [ 1 , 3 , 4 ] had already been utilized to detect FEN1.…”