CHARACTERIZING THE ROLE OF THE CHROMATIN REMODELING COMPONENT ARID1A AS A SUPPRESSOR OF SPORADIC MAMMARY TUMORS IN MICE
The American Cancer Society estimates that in the year 2017, approximately 40,000 women will die from breast cancer. The vast majority of these breast cancer cases (80-85%) are sporadic in nature, developing spontaneously within the lifetime of a woman. While there is a significant amount of knowledge regarding the genetic drivers of hereditary breast cancers, there is very little known about the genes responsible for driving sporadic breast cancers, largely in part due to the dearth of appropriate mouse models of this disease. The C3H-MCM4Chaos3(Chaos3) mouse model bears a single endogenous mutation in a gene encoding a component of the MCM2-7 replication helicase, which our lab has previously shown results in a state of chronic replication stress and downstream genomic instability, leading to a strain-specific phenotype of female mice developing spontaneous mammary adenocarcinomas. In my graduate research work, I have utilized this powerful and unique mouse model to determine the genetic drivers of these sporadic mammary tumors (MTs), based on relevance to human breast cancer data available publicly. My analyses of recurrent genomic alterations present in these Chaos3 MTs revealed that the majority of them (>80%) contained heterozygous deletions of a gene encoding the chromatin remodeling component Arid1a. Importantly, ARID1A is also frequently deleted (monoallelically) in a significant subset of human breast cancers (between 30-50%, depending on the specific study cited), based on data from The Cancer Genome Atlas (TCGA). I have characterized the pathways being altered upon overexpression of Arid1a in Chaos3 MT cells, and have identified potential direct transcriptional targets of Arid1a regulation using this in vitro system. I have further shown that the heterozygous loss of Arid1a is a critical maintenance factor for MT growth in this model, and that endogenous induction of Arid1a expression to wild-type levels is sufficient to significantly slow down MT cell proliferation in vitro. This is suggestive of a haploinsufficient role for Arid1a tumor suppression, in a manner similar to TP53, and offers an intriguing therapeutic opportunity of inducing the remaining ARID1A allele to potentially reduce MT growth in the subset of human breast cancers that retain an intact copy of this powerful tumor suppressor gene.
Genetics; Breast cancer; Molecular biology; Arid1a; Chromatin remodelers; Mouse model; SWI/SNF; Biochemistry
Schimenti, John C.
Coonrod, Scott A.; Weiss, Robert S.
Genetics & Development
PHD of Genetics & Development
Doctor of Philosophy
dissertation or thesis