title: Is there a role for base excision repair in estrogen/estrogen receptor-driven breast cancers?
abstract: Estrogen and estrogen metabolite-induced reactive oxygen species generation can promote oxidative DNA base damage. If unrepaired, base damaging lesions could accelerate mutagenesis, leading to a "mutator phenotype" characterized by aggressive behavior in estrogen-estrogen receptor (ER)-driven breast cancer. To test this hypothesis, we investigated 1406 ER(+) early-stage breast cancers with 20 years' long-term clinical follow-up data for DNA polymerase β (pol β), flap endonuclease 1 (FEN1), AP endonuclease 1 (APE1), X-ray cross-complementation group 1 protein (XRCC1), single-strand monofunctional uracil glycosylase-1 (SMUG1), poly (ADP-ribose) polymerase 1 (PARP1), ataxia telangiectasia mutated and Rad3 related (ATR), ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Chk1, Chk2, p53, breast cancer susceptibility gene 1 (BRCA1), and topoisomerase 2 (TOPO2) expression. Multivariate Cox proportional hazards model was used to calculate a DNA repair prognostic index and correlated to clinicopathological variables and survival outcomes. Key base excision repair (BER) proteins, including XRCC1, APE1, SMUG1, and FEN1, were independently associated with poor breast cancer-specific survival (BCSS) (ps≤0.01). Multivariate Cox model stratified patients into four distinct prognostic sub-groups with worsening BCSS (ps<0.01). In addition, compared with prognostic sub-group 1, sub-groups 2, 3, and 4 manifest increasing tumor size, grade, mitosis, pleomorphism, differentiation, lymphovascular invasion, high Ki67, loss of Bcl-2, luminal B phenotype (ps≤0.01), and poor survival, including in patients who received tamoxifen adjuvant therapy (p<0.00001). Our observation supports the hypothesis that BER-directed stratification could inform appropriate therapies in estrogen-ER-driven breast cancers. Antioxid.
authors.affiliation: 1 Department of Oncology, Nottingham University Hospitals , Nottingham, United Kingdom .
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.forename: Christina
authors.initials: C
authors.lastname: Perry
authors.forename: Arvind
authors.initials: A
authors.lastname: Arora
authors.forename: Nicola
authors.initials: N
authors.lastname: Thompson
authors.forename: Rachel
authors.initials: R
authors.lastname: Doherty
authors.forename: Paul M
authors.initials: PM
authors.lastname: Moseley
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.forename: Stephen Y T
authors.initials: SY
authors.lastname: Chan
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008137:Longitudinal Studies; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate; D051981:Uracil-DNA Glycosidase / Q000235:genetics / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D045585:Flap Endonucleases; C468317:FEN1 protein, human; C498095:SMUG1 protein, human; D051981:Uracil-DNA Glycosidase; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
references.citation: Cancer Res. 2001 Oct 15;61(20):7488-94
references.pmid: 11606384
references.citation: Mol Oncol. 2014 May;8(3):520-32
references.pmid: 24462520
references.citation: J Steroid Biochem Mol Biol. 2011 Jul;125(3-5):169-80
references.pmid: 21397019
references.citation: Mol Oncol. 2014 Oct;8(7):1326-38
references.pmid: 24880630
references.citation: Nucleic Acids Res. 2013 Apr 1;41(6):3483-90
references.pmid: 23408852
references.citation: Cancer Res. 2013 Mar 1;73(5):1621-34
references.pmid: 23253910
references.citation: Mol Endocrinol. 2007 Jul;21(7):1569-80
references.pmid: 17488975
references.citation: Steroids. 2013 Feb;78(2):161-70
references.pmid: 23178278
references.citation: Cold Spring Harb Perspect Biol. 2013 Aug 01;5(8):a012724
references.pmid: 23813586