Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer
| Autor: | Rossanna C. Pezo, Trevor J. Pugh, Mark Dowar, David W. Cescon, Ken Kron, Jennifer Silvester, Tak W. Mak, Mathieu Lupien, Benjamin Haibe-Kains, Aislinn E. Treloar, S. Y. Cindy Yang, Philippe L. Bedard, Richard C Sallari, Parisa Mazrooei, Kinjal Desai, Kelsie L. Thu, Xue Wu, Nicholas A Sinnott-Armstrong, Swneke D. Bailey |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Estrogen receptor Breast Neoplasms Regulatory Sequences Nucleic Acid Biology medicine.disease_cause Polymorphism Single Nucleotide Article 03 medical and health sciences Breast cancer Cell Line Tumor Genetics medicine Humans Enhancer Regulation of gene expression Mutation Estrogen Receptor alpha Cancer medicine.disease Gene Expression Regulation Neoplastic body regions 030104 developmental biology Regulatory sequence MCF-7 Cells Female CRISPR-Cas Systems Estrogen receptor alpha Transcription Factors |
| Zdroj: | Nature genetics |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/ng.3650 |
| Popis: | Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer. |
| Databáze: | OpenAIRE |
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