Breast tumors often display extreme genetic heterogeneity characterized by hundreds of gross chromosomal aberrations and tens of thousands of somatic mutations. Tumor evolution is thought to be ongoing and driven by multiplemutagenic processes. Amajor outstanding question iswhether primary tumors have preexistingmutations for therapy resistance or whether additional DNA damage and mutagenesis are necessary. Drug resistance is a key measure of tumor evolvability. If a resistancemutation preexists at the time of primary tumor presentation, then the intended therapy is likely to fail. However, if resistance does not preexist, then ongoing mutational processes still have the potential to undermine therapeutic efficacy. The antiviral enzyme APOBEC3B (apolipoprotein B mRNAediting enzyme, catalytic polypeptide-like 3B) preferentially deaminates DNA C-To-U, which results in signature C-To-T and C-To-G mutations commonly observed in breast tumors.We use clinical data and xenograft experiments to ask whether APOBEC3B contributes to ongoing breast tumor evolution and resistance to the selective estrogen receptormodulator, tamoxifen. First, APOBEC3B levels in primary estrogen receptor-positive (ER+) breast tumors inversely correlate with the clinical benefit of tamoxifen in the treatment ofmetastatic ER+ disease. Second, APOBEC3B depletion inanER+ breast cancer cell line results in prolonged tamoxifen responses in murine xenograft experiments. Third, APOBEC3B overexpression accelerates the development of tamoxifen resistance in murine xenograft experiments by a mechanism that requires the enzyme's catalytic activity. These studies combine to indicate that APOBEC3B promotes drug resistance in breast cancer and that inhibiting APOBEC3B-dependent tumor evolvability may be an effective strategy to improve efficacies of targeted cancer therapies.2016
Bibliographical noteFunding Information:
We thank several laboratory members for thoughtful comments. Funding: Animal studies were supported by the Department of Defense Breast Cancer Research Program (BC121347), the Jimmy V Foundation for Cancer Research, and the Prospect Creek Foundation. Additional support for cancer research in the Harris laboratory was provided by the Howard Hughes Medical Institute, Norwegian Centennial Chair Program, and Minnesota Ovarian Cancer Alliance. An NSF Graduate Research Fellowship provided salary support for G.J.S. NIH grant T32 CA009138 provided partial salary support for B.L. Clinical studies were supported by Cancer Genomics Netherlands (A.M.S. and J.W.M.M.), Netherlands Organisation for Scientific Research (NWO) (J.W.M.M.), and European Research Council Advanced Grant no. 322737 (J.A.F.). Statistical analyses were supported by NIH grant P30 CA77598 using the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota (R.I.V.). R.S.H. is an investigator of the Howard Hughes Medical Institute
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