An intronic polymorphism associated with increased XRCC1 expression, reduced apoptosis and familial breast cancer.
XRCC1 coordinates the activities of DNA polymerase-beta and DNA ligase for base excision repair of oxidative DNA damage. In addition, there is some evidence that XRCC1 is a negative regulator of apoptosis. Single nucleotide polymorphisms in XRCC1 have been inconsistently associated with breast cancer risk. We evaluated XRCC1 gene expression in breast cancer cell lines and carcinogen-induced apoptosis in benign breast epithelial cells in relation to XRCC1 genotypes. XRCC1 IVS10+141G>A was associated with increased expression of XRCC1 mRNA and protein, and reduced apoptosis in response to benzo-[a]-pyrene or ionizing radiation, but XRCC1 R399Q was not. These genotypes were also assessed in a clinic-based sample that included 190 breast cancer patients with a family history of breast cancer and 95 controls with no family history of breast cancer. Heterozygous XRCC1 IVS10+141G>A was associated with an increased breast cancer risk (O.R. = 1.7, 95% C.I. 1.016-2.827, P = 0.04) as was homozygous XRCC1 IVS10+141G>A (O.R. = 4.7, 95% C.I. 1.028-21.444, P = 0.03). XRCC1 R399Q was not associated with breast cancer (O.R. 1.00, 95% C.I. 0.61-1.64). The XRCC1 IVS10+141G>A locus is centered in a sequence that is nearly identical to the consensus binding site for the PLAG1 transcription factor. XRCC1 IVS10+141G>A is an intronic polymorphism that is associated with XRCC1 expression, apoptosis and familial breast cancer. It may occur within an intronic regulatory sequence.
Bu
Dawei
D
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9155, USA.
Tomlinson
Gail
G
Lewis
Cheryl M
CM
Zhang
Cindy
C
Kildebeck
Eric
E
Euhus
David M
DM
D000225:Adenine; D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005787:Gene Frequency; D005838:Genotype; D006147:Guanine; D006801:Humans; D007438:Introns / Q000235:genetics*; D016015:Logistic Models; D008698:Mesylates / Q000494:pharmacology; D008875:Middle Aged; D008969:Molecular Sequence Data; D016017:Odds Ratio; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects; D000076105:X-ray Repair Cross Complementing Protein 1
D002273:Carcinogens; D004268:DNA-Binding Proteins; D008698:Mesylates; D012333:RNA, Messenger; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C045880:methanesulfonic acid; D001564:Benzo(a)pyrene; D006147:Guanine; D000225:Adenine