Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

Abstract

FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p=4.89 × 10−57), high mitotic index (p=5.25 × 10−28), pleomorphism (p=6.31 × 10−19), ER negative (p=9.02 × 10−35), PR negative (p=9.24 × 10−24), triple negative phenotype (p=6.67 × 10−21), PAM50.Her2 (p=5.19 × 10−13), PAM50.Basal (p=2.7 × 10−41), PAM50.LumB (p=1.56 × 10−26), integrative molecular cluster 1 (intClust.1) (p=7.47 × 10−12), intClust.5 (p=4.05 × 10−12) and intClust. 10 (p=7.59 × 10−38) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p= 4.4 × 10−16) and multivariate analysis (p= 9.19 × 10−7). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps<0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps<0.05). In ER positive as well as in ER negative tumours, FEN1 protein overexpression is associated with poor survival in univariate and multivariate analysis (ps<0.01). In ovarian epithelial cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps<0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer.

Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer

“…In addition, high BLM mRNA level is also frequently seen in intClust 5 (HER2 enriched with worst survival), intClust 9 (8q cis-acting/20q-amplified mixed subgroup), and intClust 1 (17q23/20q cisacting luminal B subgroup) subgroups that also manifest an aggressive phenotype. On the other hand, low BLM mRNA level is linked to intClust 4 (includes both ER þ and ER À cases with a flat copy number landscape and termed the "CNA-devoid" (15). Interestingly, BLM has been shown to stimulate FEN1 activity in a preclinical study (26).…”

“…Patient demographics are summarized in Supplementary Table S3. This is a well-characterized series of patients with long-term follow-up that have been investigated in a wide range of biomarker studies (12)(13)(14)(15)(16)(17)(18)(19)(20). All patients were treated in a uniform way in a single institution with standard surgery (mastectomy or wide local excision) with radiotherapy.…”

“…The TMAs were immunohistochemically profiled for BLM and other biologic antibodies (Supplementary Table S4) as previously described (12)(13)(14)(15)(16)(17)(18)(19)(20). Immunohistochemical (IHC) staining was performed using the Thermo Scientific Shandon Sequenza chamber system (REF: 72110017), in combination with the Novolink Max Polymer Detection System (RE7280-K: 1,250 tests), and the Leica Bond Primary Antibody Diluent (AR9352), each used according to the manufacturer's instructions (Leica Microsystems).…”

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells

“…Previous reports have demonstrated that FEN1 is dysregulated in breast cancer and multiple other cancerous tissues (23)(24)(25). High expression of FEN1 is associated with clinicopathological significance and poor survival (26), suggesting that FEN1 has an important role in the development of breast cancer. It has previously been demonstrated that anticancer therapies are able to induce FEN1 expression (5), and inhibition of FEN1 combined with DNA injury agents results in increased inhibition of proliferation via endogenous DNA damage (12,(27)(28)(29).…”

DNA Repair Endonucleases: Physiological Roles and Potential as Drug Targets

“…[58][59][60][61][62] However, in human studies, FEN1 has frequently been shown to be overexpressed in a number of tumors, including breast, ovarian, colorectal, stomach, lung, and kidney cancers, and is associated with resistance to therapy due to increased DNA repair capacity. 50,57,63,64 It has recently been shown in a large cohort of patients with breast cancer that high FEN1 expression correlated to an aggressive phenotype and decreased overall survival. 63 FEN1 protein staining was observed in both the nucleus alone, cytoplasm alone, and both nucleus/cytoplasm.…”