The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer

Emily K. Law, Anieta M. Sieuwerts, Kelly Lapara, Brandon Leonard, Gabriel J. Starrett, Amy M. Molan, Nuri A. Temiz, Rachel Isaksson Vogel, Marion E. Meijer-Van Gelder, Fred C.G.J. Sweep, Paul N. Span, John A. Foekens, John W.M. Martens, Douglas Yee, Reuben S. Harris

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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 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

Original languageEnglish (US)
Article numbere1601737
JournalScience Advances
Volume2
Issue number10
DOIs
StatePublished - Oct 1 2016

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Cytosine Deaminase
Apolipoproteins B
Tamoxifen
Breast Neoplasms
Peptides
DNA
Enzymes
Heterografts
Neoplasms
Drug Resistance
Mutation
Genetic Heterogeneity
Mutagenesis
Chromosome Aberrations
Estrogen Receptors
DNA Damage
Antiviral Agents
Estrogens
Therapeutics

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Law, E. K., Sieuwerts, A. M., Lapara, K., Leonard, B., Starrett, G. J., Molan, A. M., ... Harris, R. S. (2016). The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. Science Advances, 2(10), [e1601737]. https://doi.org/10.1126/sciadv.1601737

The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. / Law, Emily K.; Sieuwerts, Anieta M.; Lapara, Kelly; Leonard, Brandon; Starrett, Gabriel J.; Molan, Amy M.; Temiz, Nuri A.; Vogel, Rachel Isaksson; Meijer-Van Gelder, Marion E.; Sweep, Fred C.G.J.; Span, Paul N.; Foekens, John A.; Martens, John W.M.; Yee, Douglas; Harris, Reuben S.

In: Science Advances, Vol. 2, No. 10, e1601737, 01.10.2016.

Research output: Contribution to journalArticle

Law, EK, Sieuwerts, AM, Lapara, K, Leonard, B, Starrett, GJ, Molan, AM, Temiz, NA, Vogel, RI, Meijer-Van Gelder, ME, Sweep, FCGJ, Span, PN, Foekens, JA, Martens, JWM, Yee, D & Harris, RS 2016, 'The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer', Science Advances, vol. 2, no. 10, e1601737. https://doi.org/10.1126/sciadv.1601737
Law EK, Sieuwerts AM, Lapara K, Leonard B, Starrett GJ, Molan AM et al. The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. Science Advances. 2016 Oct 1;2(10). e1601737. https://doi.org/10.1126/sciadv.1601737
Law, Emily K. ; Sieuwerts, Anieta M. ; Lapara, Kelly ; Leonard, Brandon ; Starrett, Gabriel J. ; Molan, Amy M. ; Temiz, Nuri A. ; Vogel, Rachel Isaksson ; Meijer-Van Gelder, Marion E. ; Sweep, Fred C.G.J. ; Span, Paul N. ; Foekens, John A. ; Martens, John W.M. ; Yee, Douglas ; Harris, Reuben S. / The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. In: Science Advances. 2016 ; Vol. 2, No. 10.
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