{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T06:04:26Z","timestamp":1775109866868,"version":"3.50.1"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Breast Cancer Res Treat"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>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).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Expression of FEN1 protein was evaluated in a large (<jats:italic>n<\/jats:italic>\u2009=\u20091015) well-characterised cohort of DCIS, comprising pure (<jats:italic>n<\/jats:italic>\u2009=\u2009776) and mixed (DCIS coexists with invasive breast cancer (IBC);<jats:italic>n<\/jats:italic>\u2009=\u2009239) using immunohistochemistry (IHC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s10549-021-06271-y","type":"journal-article","created":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T12:03:27Z","timestamp":1623499407000},"page":"53-63","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The prognostic significance of Flap Endonuclease 1 (FEN1) in breast ductal carcinoma in situ"],"prefix":"10.1007","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7188-2424","authenticated-orcid":false,"given":"Abdulbaqi","family":"Al-Kawaz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Islam M.","family":"Miligy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael S.","family":"Toss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar J.","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew R.","family":"Green","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srinivasan","family":"Madhusudan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emad A.","family":"Rakha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,12]]},"reference":[{"issue":"Suppl","key":"6271_CR1","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/ng1107","volume":"33","author":"A Balmain","year":"2003","unstructured":"Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33(Suppl):238\u2013244. https:\/\/doi.org\/10.1038\/ng1107","journal-title":"Nat Genet"},{"issue":"5","key":"6271_CR2","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1038\/87876","volume":"7","author":"KL Nathanson","year":"2001","unstructured":"Nathanson KL, Wooster R, Weber BL (2001) Breast cancer genetics: what we know and what we need. Nat Med 7(5):552\u2013556. https:\/\/doi.org\/10.1038\/87876","journal-title":"Nat Med"},{"issue":"7","key":"6271_CR3","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/nrm3822","volume":"15","author":"JA Marteijn","year":"2014","unstructured":"Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JH (2014) Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol 15(7):465\u2013481. https:\/\/doi.org\/10.1038\/nrm3822","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"6271_CR4","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","volume":"40","author":"A Ciccia","year":"2010","unstructured":"Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40(2):179\u2013204. https:\/\/doi.org\/10.1016\/j.molcel.2010.09.019","journal-title":"Mol Cell"},{"issue":"12 Suppl","key":"6271_CR5","doi-asserted-by":"publisher","first-page":"2635","DOI":"10.1002\/cncr.22653","volume":"109","author":"RA Rudel","year":"2007","unstructured":"Rudel RA, Attfield KR, Schifano JN, Brody JG (2007) Chemicals causing mammary gland tumors in animals signal new directions for epidemiology, chemicals testing, and risk assessment for breast cancer prevention. Cancer 109(12 Suppl):2635\u20132666. https:\/\/doi.org\/10.1002\/cncr.22653","journal-title":"Cancer"},{"key":"6271_CR6","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/1476-069x-14-14","volume":"14","author":"E Garcia","year":"2015","unstructured":"Garcia E, Hurley S, Nelson DO, Hertz A, Reynolds P (2015) Hazardous air pollutants and breast cancer risk in California teachers: a cohort study. Environmental health\u202f: a global access science source 14:14. https:\/\/doi.org\/10.1186\/1476-069x-14-14","journal-title":"Environmental health : a global access science source"},{"key":"6271_CR7","first-page":"52","volume":"810","author":"WB Grant","year":"2014","unstructured":"Grant WB (2014) Solar ultraviolet irradiance and cancer incidence and mortality. Adv Exp Med Biol 810:52\u201368","journal-title":"Adv Exp Med Biol"},{"issue":"5","key":"6271_CR8","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1517\/17425255.2015.1037277","volume":"11","author":"JC Singh","year":"2015","unstructured":"Singh JC, Lichtman SM (2015) Effect of age on drug metabolism in women with breast cancer. Expert Opin Drug Metab Toxicol 11(5):757\u2013766. https:\/\/doi.org\/10.1517\/17425255.2015.1037277","journal-title":"Expert Opin Drug Metab Toxicol"},{"issue":"1","key":"6271_CR9","doi-asserted-by":"publisher","first-page":"65","DOI":"10.2217\/whe.14.62","volume":"11","author":"Y Liu","year":"2015","unstructured":"Liu Y, Nguyen N, Colditz GA (2015) Links between alcohol consumption and breast cancer: a look at the evidence. Womens Health (Lond Engl) 11(1):65\u201377. https:\/\/doi.org\/10.2217\/whe.14.62","journal-title":"Womens Health (Lond Engl)"},{"issue":"10 Pt 1","key":"6271_CR10","first-page":"953","volume":"11","author":"PD Terry","year":"2002","unstructured":"Terry PD, Rohan TE (2002) Cigarette smoking and the risk of breast cancer in women: a review of the literature. Cancer epidemiology, biomarkers & prevention\u202f: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 11(10 Pt 1):953\u2013971","journal-title":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology"},{"issue":"4","key":"6271_CR11","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1093\/carcin\/bgg013","volume":"24","author":"B Faraglia","year":"2003","unstructured":"Faraglia B, Chen SY, Gammon MD, Zhang Y, Teitelbaum SL, Neugut AI, Ahsan H, Garbowski GC, Hibshoosh H, Lin D, Kadlubar FF, Santella RM (2003) Evaluation of 4-aminobiphenyl-DNA adducts in human breast cancer: the influence of tobacco smoke. Carcinogenesis 24(4):719\u2013725","journal-title":"Carcinogenesis"},{"issue":"2","key":"6271_CR12","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1667\/rr13515.1","volume":"181","author":"CG Broustas","year":"2014","unstructured":"Broustas CG, Lieberman HB (2014) DNA damage response genes and the development of cancer metastasis. Radiat Res 181(2):111\u2013130. https:\/\/doi.org\/10.1667\/rr13515.1","journal-title":"Radiat Res"},{"issue":"2","key":"6271_CR13","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.pathol.2016.11.002","volume":"49","author":"R Ali","year":"2017","unstructured":"Ali R, Rakha EA, Madhusudan S, Bryant HE (2017) DNA damage repair in breast cancer and its therapeutic implications. Pathology 49(2):156\u2013165. https:\/\/doi.org\/10.1016\/j.pathol.2016.11.002","journal-title":"Pathology"},{"issue":"12","key":"6271_CR14","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.1007\/s10552-015-0672-7","volume":"26","author":"AJ White","year":"2015","unstructured":"White AJ, Chen J, McCullough LE, Xu X, Cho YH, Teitelbaum SL, Neugut AI, Terry MB, Hibshoosh H, Santella RM, Gammon MD (2015) Polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer: modification by gene promoter methylation in a population-based study. Cancer Causes Control 26(12):1791\u20131802. https:\/\/doi.org\/10.1007\/s10552-015-0672-7","journal-title":"Cancer Causes Control"},{"issue":"4","key":"6271_CR15","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/S1568-7864(02)00008-3","volume":"1","author":"JK Horton","year":"2002","unstructured":"Horton JK, Baker A, Berg BJ, Sobol RW, Wilson SH (2002) Involvement of DNA polymerase beta in protection against the cytotoxicity of oxidative DNA damage. DNA Repair 1(4):317\u2013333","journal-title":"DNA Repair"},{"issue":"11","key":"6271_CR16","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1158\/1541-7786.mcr-08-0269","volume":"6","author":"P Singh","year":"2008","unstructured":"Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B (2008) Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers. Molecular cancer research\u202f: MCR 6(11):1710\u20131717. https:\/\/doi.org\/10.1158\/1541-7786.mcr-08-0269","journal-title":"Molecular cancer research : MCR"},{"issue":"15","key":"6271_CR17","doi-asserted-by":"publisher","first-page":"9924","DOI":"10.1073\/pnas.152321699","volume":"99","author":"M Kucherlapati","year":"2002","unstructured":"Kucherlapati M, Yang K, Kuraguchi M, Zhao J, Lia M, Heyer J, Kane MF, Fan K, Russell R, Brown AM, Kneitz B, Edelmann W, Kolodner RD, Lipkin M, Kucherlapati R (2002) Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression. Proc Natl Acad Sci USA 99(15):9924\u20139929. https:\/\/doi.org\/10.1073\/pnas.152321699","journal-title":"Proc Natl Acad Sci USA"},{"issue":"7","key":"6271_CR18","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/nm1599","volume":"13","author":"L Zheng","year":"2007","unstructured":"Zheng L, Dai H, Zhou M, Li M, Singh P, Qiu J, Tsark W, Huang Q, Kernstine K, Zhang X, Lin D, Shen B (2007) Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nat Med 13(7):812\u2013819. https:\/\/doi.org\/10.1038\/nm1599","journal-title":"Nat Med"},{"issue":"2","key":"6271_CR19","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1111\/j.1464-410X.2006.06224.x","volume":"98","author":"JS Lam","year":"2006","unstructured":"Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS (2006) Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score. BJU Int 98(2):445\u2013451. https:\/\/doi.org\/10.1111\/j.1464-410X.2006.06224.x","journal-title":"BJU Int"},{"issue":"6","key":"6271_CR20","doi-asserted-by":"publisher","first-page":"3465","DOI":"10.1074\/jbc.M606582200","volume":"282","author":"P Singh","year":"2007","unstructured":"Singh P, Zheng L, Chavez V, Qiu J, Shen B (2007) Concerted action of exonuclease and Gap-dependent endonuclease activities of FEN-1 contributes to the resolution of triplet repeat sequences (CTG)n- and (GAA)n-derived secondary structures formed during maturation of Okazaki fragments. J Biol Chem 282(6):3465\u20133477. https:\/\/doi.org\/10.1074\/jbc.M606582200","journal-title":"J Biol Chem"},{"issue":"16","key":"6271_CR21","doi-asserted-by":"publisher","first-page":"27593","DOI":"10.18632\/oncotarget.15176","volume":"8","author":"C Kathera","year":"2017","unstructured":"Kathera C, Zhang J, Janardhan A, Sun H, Ali W, Zhou X, He L, Guo Z (2017) Interacting partners of FEN1 and its role in the development of anticancer therapeutics. Oncotarget 8(16):27593\u201327602. https:\/\/doi.org\/10.18632\/oncotarget.15176","journal-title":"Oncotarget"},{"issue":"7","key":"6271_CR22","doi-asserted-by":"publisher","first-page":"4901","DOI":"10.1074\/jbc.M007825200","volume":"276","author":"J Qiu","year":"2001","unstructured":"Qiu J, Li X, Frank G, Shen B (2001) Cell cycle-dependent and DNA damage-inducible nuclear localization of FEN-1 nuclease is consistent with its dual functions in DNA replication and repair. J Biol Chem 276(7):4901\u20134908. https:\/\/doi.org\/10.1074\/jbc.M007825200","journal-title":"J Biol Chem"},{"issue":"13","key":"6271_CR23","doi-asserted-by":"publisher","first-page":"4310","DOI":"10.1128\/mcb.00200-08","volume":"28","author":"Z Guo","year":"2008","unstructured":"Guo Z, Qian L, Liu R, Dai H, Zhou M, Zheng L, Shen B (2008) Nucleolar localization and dynamic roles of flap endonuclease 1 in ribosomal DNA replication and damage repair. Mol Cell Biol 28(13):4310\u20134319. https:\/\/doi.org\/10.1128\/mcb.00200-08","journal-title":"Mol Cell Biol"},{"issue":"16","key":"6271_CR24","doi-asserted-by":"publisher","first-page":"4975","DOI":"10.1128\/mcb.00457-08","volume":"28","author":"P Liu","year":"2008","unstructured":"Liu P, Qian L, Sung JS, de Souza-Pinto NC, Zheng L, Bogenhagen DF, Bohr VA, Wilson DM 3rd, Shen B, Demple B (2008) Removal of oxidative DNA damage via FEN1-dependent long-patch base excision repair in human cell mitochondria. Mol Cell Biol 28(16):4975\u20134987. https:\/\/doi.org\/10.1128\/mcb.00457-08","journal-title":"Mol Cell Biol"},{"issue":"6","key":"6271_CR25","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1016\/S1097-2765(01)00272-6","volume":"7","author":"S Hasan","year":"2001","unstructured":"Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hubscher U, Hottiger MO (2001) Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300. Mol Cell 7(6):1221\u20131231","journal-title":"Mol Cell"},{"issue":"10","key":"6271_CR26","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1038\/nchembio.422","volume":"6","author":"Z Guo","year":"2010","unstructured":"Guo Z, Zheng L, Xu H, Dai H, Zhou M, Pascua MR, Chen QM, Shen B (2010) Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding. Nat Chem Biol 6(10):766\u2013773. https:\/\/doi.org\/10.1038\/nchembio.422","journal-title":"Nat Chem Biol"},{"issue":"4","key":"6271_CR27","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/emm.1998.37","volume":"30","author":"IS Kim","year":"1998","unstructured":"Kim IS (1998) Down-regulation of human FEN-1 gene expression during differentiation of promyelocytic leukemia cells. Exp Mol Med 30(4):252\u2013256. https:\/\/doi.org\/10.1038\/emm.1998.37","journal-title":"Exp Mol Med"},{"issue":"2\u20133","key":"6271_CR28","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/S0167-4889(00)00029-X","volume":"1496","author":"IS Kim","year":"2000","unstructured":"Kim IS, Lee MY, Lee IH, Shin SL, Lee SY (2000) Gene expression of flap endonuclease-1 during cell proliferation and differentiation. Biochem Biophys Acta 1496(2\u20133):333\u2013340","journal-title":"Biochem Biophys Acta"},{"issue":"3","key":"6271_CR29","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1002\/(sici)1096-9896(1998110)186:3<319::aid-path184>3.0.co;2-2","volume":"186","author":"E Warbrick","year":"1998","unstructured":"Warbrick E, Coates PJ, Hall PA (1998) Fen1 expression: a novel marker for cell proliferation. J Pathol 186(3):319\u2013324. https:\/\/doi.org\/10.1002\/(sici)1096-9896(1998110)186:3%3c319::aid-path184%3e3.0.co;2-2","journal-title":"J Pathol"},{"issue":"2","key":"6271_CR30","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1034\/j.1399-0004.2001.590210.x","volume":"59","author":"CJ Otto","year":"2001","unstructured":"Otto CJ, Almqvist E, Hayden MR, Andrew SE (2001) The \u201cflap\u201d endonuclease gene FEN1 is excluded as a candidate gene implicated in the CAG repeat expansion underlying Huntington disease. Clin Genet 59(2):122\u2013127","journal-title":"Clin Genet"},{"issue":"15","key":"6271_CR31","first-page":"4499","volume":"62","author":"E LaTulippe","year":"2002","unstructured":"LaTulippe E, Satagopan J, Smith A, Scher H, Scardino P, Reuter V, Gerald WL (2002) Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Can Res 62(15):4499\u20134506","journal-title":"Can Res"},{"issue":"4","key":"6271_CR32","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1016\/s0002-9440(10)63911-9","volume":"162","author":"CA Iacobuzio-Donahue","year":"2003","unstructured":"Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M (2003) Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol 162(4):1151\u20131162. https:\/\/doi.org\/10.1016\/s0002-9440(10)63911-9","journal-title":"Am J Pathol"},{"issue":"2 Pt 1","key":"6271_CR33","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1158\/1078-0432.473.11.2","volume":"11","author":"JM Kim","year":"2005","unstructured":"Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Kim YS, Kim JG, Kim NS (2005) Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells. Clinical cancer research\u202f: an official journal of the American Association for Cancer Research 11(2 Pt 1):473\u2013482","journal-title":"Clinical cancer research : an official journal of the American Association for Cancer Research"},{"issue":"1","key":"6271_CR34","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.canlet.2004.10.035","volume":"225","author":"A Krause","year":"2005","unstructured":"Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A (2005) Genome-wide analysis of gene expression in neuroblastomas detected by mass screening. Cancer Lett 225(1):111\u2013120. https:\/\/doi.org\/10.1016\/j.canlet.2004.10.035","journal-title":"Cancer Lett"},{"issue":"46","key":"6271_CR35","doi-asserted-by":"publisher","first-page":"7243","DOI":"10.1038\/sj.onc.1206977","volume":"22","author":"M Sato","year":"2003","unstructured":"Sato M, Girard L, Sekine I, Sunaga N, Ramirez RD, Kamibayashi C, Minna JD (2003) Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer. Oncogene 22(46):7243\u20137246. https:\/\/doi.org\/10.1038\/sj.onc.1206977","journal-title":"Oncogene"},{"issue":"7","key":"6271_CR36","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1016\/j.molonc.2014.04.009","volume":"8","author":"TM Abdel-Fatah","year":"2014","unstructured":"Abdel-Fatah TM, Russell R, Albarakati N, Maloney DJ, Dorjsuren D, Rueda OM, Moseley P, Mohan V, Sun H, Abbotts R, Mukherjee A, Agarwal D, Illuzzi JL, Jadhav A, Simeonov A, Ball G, Chan S, Caldas C, Ellis IO, Wilson DM 3rd, Madhusudan S (2014) Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer. Mol Oncol 8(7):1326\u20131338. https:\/\/doi.org\/10.1016\/j.molonc.2014.04.009","journal-title":"Mol Oncol"},{"issue":"12","key":"6271_CR37","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1038\/s41379-018-0086-7","volume":"31","author":"IM Miligy","year":"2018","unstructured":"Miligy IM, Gorringe KL, Toss MS, Al-Kawaz AA, Simpson P, Diez-Rodriguez M, Nolan CC, Ellis IO, Green AR, Rakha EA (2018) Thioredoxin-interacting protein is an independent risk stratifier for breast ductal carcinoma in situ. Mod Pathol 31(12):1807\u20131815. https:\/\/doi.org\/10.1038\/s41379-018-0086-7","journal-title":"Mod Pathol"},{"issue":"16","key":"6271_CR38","doi-asserted-by":"publisher","first-page":"2784","DOI":"10.1200\/JCO.2009.25.6529","volume":"28","author":"MEH Hammond","year":"2010","unstructured":"Hammond MEH, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FCG, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American Society of Clinical Oncology\/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28(16):2784\u20132795. https:\/\/doi.org\/10.1200\/JCO.2009.25.6529","journal-title":"J Clin Oncol"},{"issue":"2","key":"6271_CR39","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1136\/jclinpath-2014-202571","volume":"68","author":"EA Rakha","year":"2015","unstructured":"Rakha EA, Pinder SE, Bartlett JMS, Ibrahim M, Starczynski J, Carder PJ, Provenzano E, Hanby A, Hales S, Lee AHS, Ellis IO, Committee NC (2015) Updated UK Recommendations for HER2 assessment in breast cancer. J Clin Pathol 68(2):93\u201399. https:\/\/doi.org\/10.1136\/jclinpath-2014-202571","journal-title":"J Clin Pathol"},{"issue":"10","key":"6271_CR40","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1038\/s41379-019-0286-9","volume":"32","author":"MS Toss","year":"2019","unstructured":"Toss MS, Miligy IM, Gorringe KL, Aleskandarany MA, Alkawaz A, Mittal K, Aneja R, Ellis IO, Green AR, Rakha EA (2019) Collagen XI alpha-1 chain is an independent prognostic factor in breast ductal carcinoma in situ. Mod Pathol 32(10):1460\u20131472. https:\/\/doi.org\/10.1038\/s41379-019-0286-9","journal-title":"Mod Pathol"},{"issue":"7403","key":"6271_CR41","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1038\/nature10983","volume":"486","author":"C Curtis","year":"2012","unstructured":"Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346\u2013352. https:\/\/doi.org\/10.1038\/nature10983","journal-title":"Nature"},{"issue":"2","key":"6271_CR42","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1007\/s10549-017-4267-8","volume":"164","author":"E Chrysanthou","year":"2017","unstructured":"Chrysanthou E, Gorringe KL, Joseph C, Craze M, Nolan CC, Diez-Rodriguez M, Green AR, Rakha EA, Ellis IO, Mukherjee A (2017) Phenotypic characterisation of breast cancer: the role of CDC42. Breast Cancer Res Treat 164(2):317\u2013325. https:\/\/doi.org\/10.1007\/s10549-017-4267-8","journal-title":"Breast Cancer Res Treat"},{"issue":"21","key":"6271_CR43","doi-asserted-by":"publisher","first-page":"7252","DOI":"10.1158\/1078-0432.ccr-04-0713","volume":"10","author":"RL Camp","year":"2004","unstructured":"Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clinical Cancer Res 10(21):7252\u20137259. https:\/\/doi.org\/10.1158\/1078-0432.ccr-04-0713","journal-title":"Clinical Cancer Res"},{"issue":"4","key":"6271_CR44","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1093\/jnci\/92.4.313","volume":"92","author":"FM Waldman","year":"2000","unstructured":"Waldman FM, DeVries S, Chew KL, Moore DH 2nd, Kerlikowske K, Ljung BM (2000) Chromosomal alterations in ductal carcinomas in situ and their in situ recurrences. J Natl Cancer Inst 92(4):313\u2013320. https:\/\/doi.org\/10.1093\/jnci\/92.4.313","journal-title":"J Natl Cancer Inst"},{"key":"6271_CR45","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3389\/fonc.2017.00248","volume":"7","author":"KL Gorringe","year":"2017","unstructured":"Gorringe KL, Fox SB (2017) Ductal carcinoma in situ biology, biomarkers, and diagnosis. Front Oncol 7:248. https:\/\/doi.org\/10.3389\/fonc.2017.00248","journal-title":"Front Oncol"},{"issue":"12","key":"6271_CR46","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1007\/s10552-015-0670-9","volume":"26","author":"KM O'Brien","year":"2015","unstructured":"O\u2019Brien KM, Sun J, Sandler DP, DeRoo LA, Weinberg CR (2015) Risk factors for young-onset invasive and in situ breast cancer. Cancer causes & control\u202f: CCC 26(12):1771\u20131778. https:\/\/doi.org\/10.1007\/s10552-015-0670-9","journal-title":"Cancer causes & control : CCC"},{"key":"6271_CR47","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.ebiom.2016.11.012","volume":"14","author":"L He","year":"2016","unstructured":"He L, Zhang Y, Sun H, Jiang F, Yang H, Wu H, Zhou T, Hu S, Kathera CS, Wang X, Chen H, Li H, Shen B, Zhu Y, Guo Z (2016) Targeting DNA flap endonuclease 1 to impede breast cancer progression. EBioMedicine 14:32\u201343. https:\/\/doi.org\/10.1016\/j.ebiom.2016.11.012","journal-title":"EBioMedicine"},{"issue":"1","key":"6271_CR48","doi-asserted-by":"publisher","first-page":"e1003254","DOI":"10.1371\/journal.pgen.1003254","volume":"9","author":"DM van Pel","year":"2013","unstructured":"van Pel DM, Barrett IJ, Shimizu Y, Sajesh BV, Guppy BJ, Pfeifer T, McManus KJ, Hieter P (2013) An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-spectrum target for anticancer therapeutic development. PLoS Genet 9(1):e1003254. https:\/\/doi.org\/10.1371\/journal.pgen.1003254","journal-title":"PLoS Genet"},{"issue":"1","key":"6271_CR49","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.ajpath.2017.09.011","volume":"188","author":"K Zhang","year":"2018","unstructured":"Zhang K, Keymeulen S, Nelson R, Tong TR, Yuan YC, Yun X, Liu Z, Lopez J, Raz DJ, Kim JY (2018) Overexpression of flap endonuclease 1 correlates with enhanced proliferation and poor prognosis of non-small-cell lung cancer. Am J Pathol 188(1):242\u2013251. https:\/\/doi.org\/10.1016\/j.ajpath.2017.09.011","journal-title":"Am J Pathol"},{"issue":"5","key":"6271_CR50","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.3892\/ijmm.2014.1682","volume":"33","author":"K Wang","year":"2014","unstructured":"Wang K, Xie C, Chen D (2014) Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis. Int J Mol Med 33(5):1268\u20131274. https:\/\/doi.org\/10.3892\/ijmm.2014.1682","journal-title":"Int J Mol Med"},{"issue":"6","key":"6271_CR51","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1002\/1878-0261.12058","volume":"11","author":"L He","year":"2017","unstructured":"He L, Luo L, Zhu H, Yang H, Zhang Y, Wu H, Sun H, Jiang F, Kathera CS, Liu L, Zhuang Z, Chen H, Pan F, Hu Z, Zhang J, Guo Z (2017) FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer. Mol Oncol 11(6):640\u2013654. https:\/\/doi.org\/10.1002\/1878-0261.12058","journal-title":"Mol Oncol"},{"issue":"11","key":"6271_CR52","doi-asserted-by":"publisher","first-page":"5634","DOI":"10.1093\/nar\/gky313","volume":"46","author":"JR Becker","year":"2018","unstructured":"Becker JR, Gallo D, Leung W, Croissant T, Thu YM, Nguyen HD, Starr TK, Brown GW, Bielinsky AK (2018) Flap endonuclease overexpression drives genome instability and DNA damage hypersensitivity in a PCNA-dependent manner. Nucleic Acids Res 46(11):5634\u20135650. https:\/\/doi.org\/10.1093\/nar\/gky313","journal-title":"Nucleic Acids Res"},{"issue":"2","key":"6271_CR53","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1677\/jme.1.01677","volume":"34","author":"JG Moggs","year":"2005","unstructured":"Moggs JG, Murphy TC, Lim FL, Moore DJ, Stuckey R, Antrobus K, Kimber I, Orphanides G (2005) Anti-proliferative effect of estrogen in breast cancer cells that re-express ERalpha is mediated by aberrant regulation of cell cycle genes. J Mol Endocrinol 34(2):535\u2013551. https:\/\/doi.org\/10.1677\/jme.1.01677","journal-title":"J Mol Endocrinol"},{"key":"6271_CR54","doi-asserted-by":"publisher","first-page":"673790","DOI":"10.5402\/2011\/673790","volume":"2011","author":"A Dobrescu","year":"2011","unstructured":"Dobrescu A, Chang M, Kirtani V, Turi GK, Hennawy R, Hindenburg AA (2011) Study of estrogen receptor and progesterone receptor expression in breast ductal carcinoma in situ by immunohistochemical staining in er\/pgr-negative invasive breast cancer. ISRN Oncology 2011:673790. https:\/\/doi.org\/10.5402\/2011\/673790","journal-title":"ISRN Oncology"},{"issue":"7","key":"6271_CR55","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1093\/jnci\/djh097","volume":"96","author":"SM Swain","year":"2004","unstructured":"Swain SM, Wilson JW, Mamounas EP, Bryant J, Wickerham DL, Fisher B, Paik S, Wolmark N (2004) Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer. J Natl Cancer Inst 96(7):516\u2013523. https:\/\/doi.org\/10.1093\/jnci\/djh097","journal-title":"J Natl Cancer Inst"},{"issue":"21","key":"6271_CR56","doi-asserted-by":"publisher","first-page":"4687","DOI":"10.1200\/jco.2005.04.076","volume":"23","author":"G Arpino","year":"2005","unstructured":"Arpino G, Weiss HL, Clark GM, Hilsenbeck SG, Osborne CK (2005) Hormone receptor status of a contralateral breast cancer is independent of the receptor status of the first primary in patients not receiving adjuvant tamoxifen. J Clin Oncol 23(21):4687\u20134694. https:\/\/doi.org\/10.1200\/jco.2005.04.076","journal-title":"J Clin Oncol"},{"key":"6271_CR57","doi-asserted-by":"publisher","first-page":"232","DOI":"10.7150\/jca.2.232","volume":"2","author":"SA Lari","year":"2011","unstructured":"Lari SA, Kuerer HM (2011) Biological markers in DCIS and risk of breast recurrence: a systematic review. J Cancer 2:232\u2013261","journal-title":"J Cancer"},{"issue":"7","key":"6271_CR58","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1210\/me.2006-0519","volume":"21","author":"JR Schultz-Norton","year":"2007","unstructured":"Schultz-Norton JR, Walt KA, Ziegler YS, McLeod IX, Yates JR, Raetzman LT, Nardulli AM (2007) The deoxyribonucleic acid repair protein flap endonuclease-1 modulates estrogen-responsive gene expression. Molecular endocrinology (Baltimore, Md) 21(7):1569\u20131580. https:\/\/doi.org\/10.1210\/me.2006-0519","journal-title":"Molecular endocrinology (Baltimore, Md)"},{"issue":"8","key":"6271_CR59","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1007\/s12094-018-02019-1","volume":"21","author":"Y Wang","year":"2019","unstructured":"Wang Y, Li S, Zhu L, Zou J, Jiang X, Chen M, Chen B (2019) Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1. Clinical & translational oncology\u202f: official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 21(8):1026\u20131033. https:\/\/doi.org\/10.1007\/s12094-018-02019-1","journal-title":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico"},{"issue":"8","key":"6271_CR60","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1093\/nar\/26.8.2001","volume":"26","author":"KH Chen","year":"1998","unstructured":"Chen KH, Yakes FM, Srivastava DK, Singhal RK, Sobol RW, Horton JK, Van Houten B, Wilson SH (1998) Up-regulation of base excision repair correlates with enhanced protection against a DNA damaging agent in mouse cell lines. Nucleic Acids Res 26(8):2001\u20132007. https:\/\/doi.org\/10.1093\/nar\/26.8.2001","journal-title":"Nucleic Acids Res"}],"container-title":["Breast Cancer Research and Treatment"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10549-021-06271-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10549-021-06271-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10549-021-06271-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T22:37:32Z","timestamp":1672439852000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10549-021-06271-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,12]]},"references-count":60,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["6271"],"URL":"https:\/\/doi.org\/10.1007\/s10549-021-06271-y","relation":{},"ISSN":["0167-6806","1573-7217"],"issn-type":[{"value":"0167-6806","type":"print"},{"value":"1573-7217","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,12]]},"assertion":[{"value":"12 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no conflicts of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This work obtained ethics approval by the North West \u2013 Greater Manchester Central Research Ethics Committee under the title; Nottingham Health Science Biobank (NHSB), reference number 15\/NW\/0685. We can declare that this study is complying with the Helsinki declaration.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All patients included in this study were consented.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed Consent"}},{"value":"This article does not contain any studies with human participants or animals performed by any of the authors.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research involving human participants and\/or animals"}}]}}