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APOBEC3B is an enzymatic source of mutation in breast cancer.

ABSTRACT: Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavoured non-methylated cytosines throughout the genome, and are sometimes clustered. Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours and breast cancer cell lines. Tumours that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell-line extracts. Knockdown experiments show that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression causes cell cycle deviations, cell death, DNA fragmentation, ?-H2AX accumulation and C-to-T mutations. Our data suggest a model in which APOBEC3B-catalysed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumours evolve rapidly and manifest heterogeneity.

SUBMITTER: Burns MB

PROVIDER: S-EPMC3907282 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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APOBEC3B is an enzymatic source of mutation in breast cancer.

Burns Michael B MB Lackey Lela L Carpenter Michael A MA Rathore Anurag A Land Allison M AM Leonard Brandon B Refsland Eric W EW Kotandeniya Delshanee D Tretyakova Natalia N Nikas Jason B JB Yee Douglas D Temiz Nuri A NA Donohue Duncan E DE McDougle Rebecca M RM Brown William L WL Law Emily K EK Harris Reuben S RS

Nature 20130206 7437

Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavoured non-methylated cytosines throughout the genome, and are sometimes clustered. Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours an ...[more]

PMID: 23389445

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Project description:Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) mRNA expression is associated with the poor prognosis of estrogen receptor positive (ER+) breast cancer. However, the clinical relevance of APOBEC3B protein expression in patients with breast cancer remains unclear. The present study evaluated the association of APOBEC3B protein expression with clinicopathological features, as well as survival outcomes of patients with breast cancer. Furthermore, the association between APOBEC3B protein expression and tumor infiltrating lymphocytes (TILs) was investigated. APOBEC3B protein expression in 120 patients with breast cancer was evaluated via immunohistochemistry, using a constructed tumor microarray, and TILs were analyzed by hematoxylin and eosin staining. The relevance of APOBEC3B mRNA expression in breast cancer was assessed using a Kaplan-Meier Plotter online tool, as well as the Tumor Immune Estimation Response and The Cancer Genome Atlas databases. The present study assessed APOBEC3B expression in 116 patients with breast cancer and demonstrated that protein expression was significantly associated with ER and progesterone receptor expression, as well as different subtypes of breast cancer. Notably, APOEBC3B protein expression was significantly associated with TILs. Overall, high expression levels of APOBEC3B protein and high levels of TILs were indicative of longer disease-free survival rate. High APOBEC3B mRNA expression was associated with poor relapse-free survival rate, overall survival rate and distant metastasis-free survival rate in patients with breast cancer, particularly for the Luminal A subtype. APOBEC3B mRNA expression was also indicated to be associated with the immune status of patients with breast cancer. Overall, the results of the present study demonstrated that APOBEC3B mRNA and protein expression levels presented different prognostic values in the survival of patients with breast cancer. However, both APOBEC3B mRNA and protein expression levels were associated with TILs in breast cancer. Therefore, APOBEC3B may be a prognostic biomarker for breast cancer.

Project description:Increased APOBEC3B mRNA levels are associated with a hypermutator phenotype and poor prognosis in ER-positive breast cancer patients. In addition, a 29.5 kb deletion polymorphism of APOBEC3B, resulting in an APOBEC3A-B hybrid transcript, has been associated with an increased breast cancer risk and the hypermutator phenotype. Here we evaluated whether the APOBEC3B deletion polymorphism also associates with clinical outcome of breast cancer. Copy number analysis was performed by quantitative PCR (qPCR) in primary tumors of 1,756 Dutch breast cancer patients. The APOBEC3B deletion was found in 187 patients of whom 16 carried a two-copy deletion and 171 carried a one-copy deletion. The prognostic value of the APOBEC3B deletion for the natural course of the disease was evaluated among 1,076 lymph-node negative (LNN) patients who did not receive adjuvant systemic treatment. No association was found between APOBEC3B copy number values and the length of metastasis-free survival (MFS; hazard ratio (HR) = 1.00, 95% confidence interval (CI) = 0.90-1.11, P = 0.96). Subgroup analysis by ER status also did not reveal an association between APOBEC3B copy number values and the length of MFS. The predictive value of the APOBEC3B deletion was assessed among 329 ER-positive breast cancer patients who received tamoxifen as the first-line therapy for recurrent disease and 226 breast cancer patients who received first-line chemotherapy for recurrent disease. No association between APOBEC3B copy number values and the overall response rate (ORR) to either tamoxifen (odds ratio (OR) = 0.88, 95% CI = 0.69-1.13, P = 0.31) or chemotherapy (OR = 0.97, 95% CI = 0.71-1.33, P = 0.87) was found. Thus, in contrast to APOBEC3B mRNA levels, the APOBEC3B deletion polymorphism has neither a prognostic nor a predictive value for breast cancer patients. Although a correlation exists between APOBEC3B copy number and mRNA expression, it is relatively weak. This suggests that other mechanisms exist that may affect and therefore determine the prognostic value of APOBEC3B mRNA levels.

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APOBEC3B is an enzymatic source of mutation in breast cancer.

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APOBEC3B is an enzymatic source of mutation in breast cancer.

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