Targeting MSH2-MSH6 heterodimer in treating basal-like breast cancer

Abstract

______________________________ Maria Spies ______________________________ Andrean Simons-Burnett ______________________________ Munir Tanas ii ACKNOWLEDGEMENTS First and foremost, I would like to thank Dr. Weizhou Zhang for his guidance and support throughout the years. I have never met anyone who is this dedicated to science and who can see clear through any noises and obstacles so effortlessly both in life and in research. He is who I aspire to be. Thank you to Dr. Meng Wu for high-throughput screening guidance and support throughout all of the hardships. Also, thank you to Dr. Kuo-Kuang Wen for lending his support and for countless interesting conversations. I would also like to thank Nicholas Borcherding for bioinformatics support and analysis throughout the years. He inspired me to get back into programming. It's really amazing what we can do with computers these days. Thanks Edward Cho for assistance for the past few months. You will carry the torch from here on out with Nick. So good luck guys. Also, to the rest of the lab members: Wei, Paige, Ryan, Gaurav, Kawther, and Ajay (my brother from another mother), thanks for all the help. Working in the lab wouldn't have been as enjoyable without you guys. I would also like to thank my thesis committee for helpful advices they have given me. Last but not least, thank you Dr. Waldschmidt for giving me this great opportunity to experience what scientists actually go through. I remember when I was first applying for graduate schools, I was genuinely curious about what it would really feel like to be knee deep in scientific research. In the end, I got more than what I bargained for and I will carry them with me for the rest of my life. iii ABSTRACT To identify novel therapeutic targets for basal-like breast cancer (BLBC) subtype, we investigated several DNA repair mechanisms associated with maintenance of high genomic instability for cell survival in cancer cells. We identified that the expressions of mismatch repair proteins, MutS protein homolog 2 and 6 (referred to as MSH2/6 hereafter), are elevated across BLBC samples compared to other breast cancer subtypes. High expression level of MSH2/6 in BLBC is associated with worse prognosis and survivability for patients. Therefore, we knocked out MSH2/6 in BLBC cell lines and performed in vivo xenograft and syngeneic mice model studies to find significant attenuation of tumor growth in MSH2 KO group. Also, MSH2/6-deficient BLBC cells have a increased rate of mutations. Additionally, we tested the efficacy of conventional chemotherapeutics and radiation treatment that would further tip the genomic instability in MSH2/6-deficient BLBC cells towards cell death, but found them to be ineffective in vivo. With our focus on improving BLBC therapeutics, we performed highthroughput screening of 1280 FDA-approved compounds to discover that calcium channel blockers preferentially destroy MSH2/6-deficient BLBC cells over MSH2/6proficient BLBC cells. This was likely due to association of significantly mutated pathways that involved...