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Ha NH, Long J, Cai Q, et al. The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer. PLoS Genet. 2016;12(9):e1006267doi: 10.1371/journal.pgen.1006267.
Ha, N. H., Long, J., Cai, Q., Shu, X. O., & Hunter, K. W. (2016). The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer. PLoS genetics, 12(9), e1006267. https://doi.org/10.1371/journal.pgen.1006267
Ha, Ngoc-Han, et al. "The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer." PLoS genetics vol. 12,9 (2016): e1006267. doi: https://doi.org/10.1371/journal.pgen.1006267
Ha NH, Long J, Cai Q, Shu XO, Hunter KW. The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer. PLoS Genet. 2016 Sep 22;12(9):e1006267. doi: 10.1371/journal.pgen.1006267. eCollection 2016 Sep. PMID: 27656887; PMCID: PMC5033489.
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PLoS Genet. 2016 Sep 22;12(9):e1006267. doi: 10.1371/journal.pgen.1006267. eCollection 2016 Sep.

The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer.

PLoS genetics

Ngoc-Han Ha, Jirong Long, Qiuyin Cai, Xiao Ou Shu, Kent W Hunter

Affiliations

  1. Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  2. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

PMID: 27656887 PMCID: PMC5033489 DOI: 10.1371/journal.pgen.1006267

Abstract

Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies.

Conflict of interest statement

The authors have declared that no competing interests exist.

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