Validation of Arid1a as a Mammary Tumor Driver in Mice

다국어 초록 (Multilingual Abstract)

Distinguishing commonly deleted genes as drivers or passengers of human cancers are key to delineating mechanisms of tumor initiation. The “Chaos3” mouse model of spontaneous breast cancer carries a missense mutation in MCM4 (minichromosome maintenance 4), causing destabilization of the MCM2‐7 replicative helicase, which in turn causes elevated genomic instability. Approximately 80% of female mice homozygous for this mutation in the C3H/FeJ background develop mammary tumors with an average latency of 12 months. Genomic analysis of these tumors revealed that ~70% had monoallelic deletion of tumor suppressor Arid1a. Arid1a is a member of the SWI/SNF chromatin remodeling complex and is responsible for conferring specificity of SWI/SNF complexes to their targets. Previous studies in the lab have shown that introduction of a second Arid1a allele in monoallelically deleted, cultured tumor cells rescued the tumorgenic phenotype following transplantation into host mammary glands. We propose that deletion of Arid1a early in postnatal development is one driver of Chaos3 mammary tumors. Here, we will perform intraductal mammary injections of adeno‐cre virus into Chaos3 females bearing a floxed Arid1a allele. Loss of Arid1a has been implicated as a driver of tumorigenesis in many cancers such as clear cell ovarian carcinoma and endometrioid carcinoma, and is deleted in ~5–11% of human breast cancers. Identifying Arid1a as a driver of mammary tumors in Chaos3 mice would validate its potential role in development of sporadic breast cancer in people.
Support or Funding Information
Breast Cancer Coalition of Rochester
This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.