Estrogen Drives Cellular Transformation and Mutagenesis in Cells Expressing the Breast Cancer-Associated R438W DNA Polymerase Lambda Protein.
Mol Cancer Res
; 14(11): 1068-1077, 2016 11.
Article
em En
| MEDLINE
| ID: mdl-27621267
Repair of DNA damage is critical for maintaining the genomic integrity of cells. DNA polymerase lambda (POLL/Pol λ) is suggested to function in base excision repair (BER) and nonhomologous end-joining (NHEJ), and is likely to play a role in damage tolerance at the replication fork. Here, using next-generation sequencing, it was discovered that the POLL rs3730477 single-nucleotide polymorphism (SNP) encoding R438W Pol λ was significantly enriched in the germlines of breast cancer patients. Expression of R438W Pol λ in human breast epithelial cells induces cellular transformation and chromosomal aberrations. The role of estrogen was assessed as it is commonly used in hormone replacement therapies and is a known breast cancer risk factor. Interestingly, the combination of estrogen treatment and the expression of the R438W Pol λ SNP drastically accelerated the rate of transformation. Estrogen exposure produces 8-oxoguanine lesions that persist in cells expressing R438W Pol λ compared with wild-type (WT) Pol λ-expressing cells. Unlike WT Pol λ, which performs error-free bypass of 8-oxoguanine lesions, expression of R438W Pol λ leads to an increase in mutagenesis and replicative stress in cells treated with estrogen. Together, these data suggest that individuals who carry the rs3730477 POLL germline variant have an increased risk of estrogen-associated breast cancer. IMPLICATIONS: The Pol λ R438W mutation can serve as a biomarker to predict cancer risk and implicates that treatment with estrogen in individuals with this mutation may further increase their risk of breast cancer. Mol Cancer Res; 14(11); 1068-77. ©2016 AACR.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Transformação Celular Neoplásica
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Mutação em Linhagem Germinativa
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DNA Polimerase beta
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Estrogênios
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Female
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Humans
Idioma:
En
Revista:
Mol Cancer Res
Assunto da revista:
BIOLOGIA MOLECULAR
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NEOPLASIAS
Ano de publicação:
2016
Tipo de documento:
Article