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

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...

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Bibliographic Details
Published in:Science advances 2016-10, Vol.2 (10), p.e1601737
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Breast Neoplasms - drug therapy
Breast Neoplasms - enzymology
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Cytidine Deaminase - genetics
Cytidine Deaminase - metabolism
Drug Resistance, Neoplasm
Female
Gene Deletion
Health and Medicine
Heterografts
Humans
MCF-7 Cells
Mice
Mice, Nude
Minor Histocompatibility Antigens - genetics
Minor Histocompatibility Antigens - metabolism
Neoplasm Transplantation
SciAdv r-articles
Tamoxifen - pharmacology
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.1601737