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An intronic polymorphism associated with increased XRCC1 expression, reduced apoptosis and familial breast cancer

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Abstract

XRCC1 coordinates the activities of DNA polymerase-β 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.

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Authors and Affiliations

  1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, USA

    Dawei Bu, Gail Tomlinson, Cheryl M. Lewis, Cindy Zhang, Eric Kildebeck & David M. Euhus

  2. E6.222 Division of Surgical Oncology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9155, USA

    David M. Euhus

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  1. Dawei Bu
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  2. Gail Tomlinson
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  3. Cheryl M. Lewis
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Correspondence to David M. Euhus.

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Supported by: Mary Kay Ash Charitable Foundation and Charles Solomon Foundation.

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Bu, D., Tomlinson, G., Lewis, C.M. et al. An intronic polymorphism associated with increased XRCC1 expression, reduced apoptosis and familial breast cancer. Breast Cancer Res Treat 99, 257–265 (2006). https://doi.org/10.1007/s10549-006-9210-3

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