Molecular mechanism and clinical impact of APOBEC3B-catalyzed mutagenesis in breast cancer

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Cancer genomic DNA sequences enable identification of all mutations and suggest targets for precision medicine. The identities and patterns of the mutations themselves also provide critical information for deducing the originating DNA damaging agents, causal molecular mechanisms, and thus additional therapeutic targets. A classic example is ultraviolet light, which crosslinks adjacent pyrimidines and leads to C-to-T transitions. A new example is the DNA cytosine deaminase APOBEC3B, which was identified recently as a source of DNA damage and mutagenesis in breast, head/neck, cervix, bladder, lung, ovary, and to lesser extents additional cancer types. This enzyme is normally an effector protein in the innate immune response to virus infection but upregulation in these cancer types causes elevated levels of genomic C-to-U deamination events, which manifest as C-to-T transitions and C-to-G transversions within distinct DNA trinucleotide contexts (preferentially 5'-TCA and 5'-TCG). Genomic C-to-U deamination events within the same trinucleotide contexts also lead to cytosine mutation clusters (kataegis), and may precipitate visible chromosomal aberrations such as translocations. Clinical studies indicate that APOBEC3B upregulation correlates with poorer outcomes for estrogen receptor-positive breast cancer patients, including shorter durations of disease-free survival and overall survival after surgery. APOBEC3B may therefore have both diagnostic and prognostic potential. APOBEC3B may also be a candidate for therapeutic targeting because inhibition of this non-essential enzyme is predicted to decrease tumor mutation rates and diminish the likelihood of undesirable mutation-dependent outcomes such as recurrence, metastasis, and the development of therapy resistant tumors.

Original languageEnglish (US)
Article number8
JournalBreast Cancer Research
Issue number1
StatePublished - Jan 21 2015

Bibliographical note

Funding Information:
T Simpson provided the original artwork for Figures 1 and 3, and A Schoenecker contributed Figure 2. D Harki, J Santini, and A Schoenecker contributed revisions. I apologize to colleagues whose work could not be cited due to reference constraints. Work in the Harris lab has been supported by grants from the US National Institutes of Health (NIH R01 AI064046 and P01 GM091743), Department of Defense Breast Cancer Research Program (BC121347), the Jimmy V Foundation for Cancer Research, the Minnesota Ovarian Cancer Alliance, the Norwegian Centennial Chair Program, the Minnesota Partnership for Biotechnology and Medical Genomics, and the Randy Shaver Cancer Research and Community Fund.

Publisher Copyright:
© Harris.


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