title: The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer.
abstract: 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 multiple mutagenic processes. A major outstanding question is whether primary tumors have preexisting mutations for therapy resistance or whether additional DNA damage and mutagenesis are necessary. Drug resistance is a key measure of tumor evolvability. If a resistance mutation 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 mRNA-editing 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 receptor modulator, tamoxifen. First, APOBEC3B levels in primary estrogen receptor-positive (ER+) breast tumors inversely correlate with the clinical benefit of tamoxifen in the treatment of metastatic ER+disease. Second, APOBEC3B depletion in an ER+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.
authors.affiliation: Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Law
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 3015 GE Rotterdam, Netherlands.
authors.forename: Anieta M
authors.identifier: 0000-0003-1341-5400
authors.initials: AM
authors.lastname: Sieuwerts
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: LaPara
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Leonard
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Gabriel J
authors.identifier: 0000-0001-5871-5306
authors.initials: GJ
authors.lastname: Starrett
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Amy M
authors.identifier: 0000-0001-8278-829X
authors.initials: AM
authors.lastname: Molan
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Nuri A
authors.identifier: 0000-0003-1416-3639
authors.initials: NA
authors.lastname: Temiz
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.; Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Rachel Isaksson
authors.initials: RI
authors.lastname: Vogel
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 3015 GE Rotterdam, Netherlands.
authors.forename: Marion E
authors.initials: ME
authors.lastname: Meijer-van Gelder
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Fred C G J
authors.identifier: 0000-0003-1103-3070
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 3015 GE Rotterdam, Netherlands.
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 3015 GE Rotterdam, Netherlands.
authors.forename: John W M
authors.identifier: 0000-0002-3428-3366
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Douglas
authors.identifier: 0000-0002-3387-4009
authors.initials: D
authors.lastname: Yee
authors.affiliation: Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D017353:Gene Deletion; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D015778:Minor Histocompatibility Antigens; D013629:Tamoxifen; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase
keywords: APOBEC3B; DNA deamination; breast cancer; cancer mutagenesis; drug resistance; tumor evolution