title: Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer.
abstract: 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.
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: Swneke D
authors: SD
authors: Bailey
authors: Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA.
authors: Kinjal
authors: K
authors: Desai
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: Ken J
authors: KJ
authors: Kron
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: Parisa
authors: P
authors: Mazrooei
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors: Nicholas A
authors: 0000-0003-4490-0601
authors: NA
authors: Sinnott-Armstrong
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: Aislinn E
authors: AE
authors: Treloar
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: Mark
authors: M
authors: Dowar
authors: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: Kelsie L
authors: KL
authors: Thu
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: David W
authors: DW
authors: Cescon
authors: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: Jennifer
authors: J
authors: Silvester
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: S Y Cindy
authors: SY
authors: Yang
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: Xue
authors: X
authors: Wu
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: Rossanna C
authors: RC
authors: Pezo
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors: Benjamin
authors: B
authors: Haibe-Kains
authors: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: Tak W
authors: TW
authors: Mak
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Philippe L
authors: PL
authors: Bedard
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: Trevor J
authors: 0000-0002-8073-5888
authors: TJ
authors: Pugh
authors: Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
authors: Richard C
authors: RC
authors: Sallari
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Mathieu
authors: 0000-0003-0929-9478
authors: M
authors: Lupien
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D014157:Transcription Factors