title: The gene desert mammary carcinoma susceptibility locus Mcs1a regulates Nr2f1 modifying mammary epithelial cell differentiation and proliferation.
abstract: Genome-wide association studies have revealed that many low-penetrance breast cancer susceptibility loci are located in non-protein coding genomic regions; however, few have been characterized. In a comparative genetics approach to model such loci in a rat breast cancer model, we previously identified the mammary carcinoma susceptibility locus Mcs1a. We now localize Mcs1a to a critical interval (277 Kb) within a gene desert. Mcs1a reduces mammary carcinoma multiplicity by 50% and acts in a mammary cell-autonomous manner. We developed a megadeletion mouse model, which lacks 535 Kb of sequence containing the Mcs1a ortholog. Global gene expression analysis by RNA-seq revealed that in the mouse mammary gland, the orphan nuclear receptor gene Nr2f1/Coup-tf1 is regulated by Mcs1a. In resistant Mcs1a congenic rats, as compared with susceptible congenic control rats, we found Nr2f1 transcript levels to be elevated in mammary gland, epithelial cells, and carcinoma samples. Chromatin looping over ∼820 Kb of sequence from the Nr2f1 promoter to a strongly conserved element within the Mcs1a critical interval was identified. This element contains a 14 bp indel polymorphism that affects a human-rat-mouse conserved COUP-TF binding motif and is a functional Mcs1a candidate. In both the rat and mouse models, higher Nr2f1 transcript levels are associated with higher abundance of luminal mammary epithelial cells. In both the mouse mammary gland and a human breast cancer global gene expression data set, we found Nr2f1 transcript levels to be strongly anti-correlated to a gene cluster enriched in cell cycle-related genes. We queried 12 large publicly available human breast cancer gene expression studies and found that the median NR2F1 transcript level is consistently lower in 'triple-negative' (ER-PR-HER2-) breast cancers as compared with 'receptor-positive' breast cancers. Our data suggest that the non-protein coding locus Mcs1a regulates Nr2f1, which is a candidate modifier of differentiation, proliferation, and mammary cancer risk.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Bart M G
authors.initials: BM
authors.lastname: Smits
authors.forename: Jill D
authors.initials: JD
authors.lastname: Haag
authors.forename: Anna I
authors.initials: AI
authors.lastname: Rissman
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.forename: Ann
authors.initials: A
authors.lastname: Tran
authors.forename: Alexi A
authors.initials: AA
authors.lastname: Schoenborn
authors.forename: Rachael C
authors.initials: RC
authors.lastname: Baird
authors.forename: Dan S
authors.initials: DS
authors.lastname: Peiffer
authors.forename: David Q
authors.initials: DQ
authors.lastname: Leinweber
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Muelbl
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Meilahn
authors.forename: Mark R
authors.initials: MR
authors.lastname: Eichelberg
authors.forename: Ning
authors.initials: N
authors.lastname: Leng
authors.forename: Christina
authors.initials: C
authors.lastname: Kendziorski
authors.forename: Manorama C
authors.initials: MC
authors.lastname: John
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Powers
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Alexander
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gould
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051838:COUP Transcription Factor I / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D002874:Chromosome Mapping; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D051379:Mice; D051381:Rats
chemical_list: D051838:COUP Transcription Factor I; C497590:Nr2f1 protein, mouse