The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice.
Human cancer genome studies have identified the SWI/SNF chromatin remodeling complex member ARID1A as one of the most frequently altered genes in several tumor types. Its role as an ovarian tumor suppressor has been supported in compound knockout mice. Here, we provide genetic and functional evidence that Arid1a is a bona fide mammary tumor suppressor, using the Chromosome aberrations occurring spontaneously 3 (Chaos3) mouse model of sporadic breast cancer. About 70% of mammary tumors that formed in these mice contained a spontaneous deletion removing all or part of one Arid1a allele. Restoration of Arid1a expression in a Chaos3 mammary tumor line with low Arid1a levels greatly impaired its ability to form tumors following injection into cleared mammary glands, indicating that ARID1A insufficiency is crucial for maintenance of these Trp53-proficient tumors. Transcriptome analysis of tumor cells before and after reintroduction of Arid1a expression revealed alterations in growth signaling and cell-cycle checkpoint pathways, in particular the activation of the TRP53 pathway. Consistent with the latter, Arid1a reexpression in tumor cells led to increased p21 (Cdkn1a) expression and dramatic accumulation of cells in G2 phase of the cell cycle. These results not only provide in vivo evidence for a tumor suppressive and/or maintenance role in breast cancer, but also indicate a potential opportunity for therapeutic intervention in ARID1A-deficient human breast cancer subtypes that retain one intact copy of the gene and also maintain wild-type TRP53 activity.
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
Nithya
N
Kartha
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
Lishuang
L
Shen
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
Carolyn
C
Maskin
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
Marsha
M
Wallace
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 jcs92@cornell.edu.
John C
JC
Schimenti
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C497837:ARID1B protein, human; C511511:Arid1a protein, mouse; C493957:Cdkn1a protein, mouse; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
Arid1a; breast cancer; cell cycle; mouse; senescence; tumor suppressor