title: Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression.
abstract: DNA flap endonuclease 1 (FEN1) plays critical roles in maintaining genome stability and integrity by participating in both DNA replication and repair. Suppression of FEN1 in cells leads to the retardation of DNA replication and accumulation of unrepaired DNA intermediates, resulting in DNA double strand breaks (DSBs) and apoptosis. Therefore, targeting FEN1 could serve as a potent strategy for cancer therapy. In this study, we demonstrated that FEN1 is overexpressed in breast cancers and is essential for rapid proliferation of cancer cells. We showed that manipulating FEN1 levels in cells alters the response of cancer cells to chemotherapeutic drugs. Furthermore, we identified a small molecular compound, SC13 that specifically inhibits FEN1 activity, thereby interfering with DNA replication and repair in vitro and in cells. SC13 suppresses cancer cell proliferation and induces chromosome instability and cytotoxicity in cells. Importantly, SC13 sensitizes cancer cells to DNA damage-inducing therapeutic modalities and impedes cancer progression in a mouse model. These findings could establish a paradigm for the treatment of breast cancer and other cancers as well.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: He
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China.
authors.forename: Yilan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Thoracic Surgery, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210000, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, Hubei, China.
authors.forename: Sencai
authors.initials: S
authors.lastname: Hu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China.
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Kathera
authors.affiliation: Isotope Laboratory, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
authors.forename: Haoyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte 91010, CA, USA.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte 91010, CA, USA; Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte 91010, CA, USA.
authors.forename: Binghui
authors.initials: B
authors.lastname: Shen
authors.affiliation: Center for New Drug Research & Development, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China. Electronic address: guozgang@gmail.com.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D045585:Flap Endonucleases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D045585:Flap Endonucleases
keywords: Breast cancer; Chemotherapeutic drug; DNA replication and repair; Flap endonuclease 1 (FEN1); Small molecular inhibitor