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Defining the Roles of Oncogenic Pik3ca Mutations and Genetic Cooperation in Mouse Models of Breast Cancer

Most human breast tumors have mutations in the growth factor/phosphatidylinositol 3’ kinase (PI3K) pathway. These can occur in genes coding for receptors, adaptor proteins, catalytic and regulatory subunits of PI3K, downstream kinases, or antagonistic tumor suppressors. While each genetic change results in elevated PI3K signaling, and all major breast cancer subtypes show pathway activation, the specific mutations involved in any one tumor may play an important role in defining tumor subtype, prognosis and sensitivity to therapy. Here, I describe mouse models of PI3K-induced breast cancer.
First I generated mice that express Pik3ca cDNA under control of the ROSA26 promoter, in a Cre-dependent and therefore tissue specific way. I have generated four strains of knock-in mice: R26-Pik3cawt, R26-Pik3caE545K, R26-Pik3caH1047R, and R26-Pik3caE545K-H1047R, which can be induced to express wild type, helical domain, kinase domain and double mutant forms of mouse p110α, respectively. Mice expressing mutant Pi3kca develop mammary tumors, but the phenotypic spectrum for each mutation is unique. Indeed, many E545K mammary tumors are
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vascularized, whereas H1047R tumors are not. Using these models, I have compared downstream signaling properties of E545K and H1047R.
The potential for improved breast cancer treatment lies in combination therapies that target more than one oncogenic pathway. To develop such treatments, we need good mouse models, and an understanding of the oncogenic network. To this end, my Pik3caH1047R model was mated to p53 and PTEN knockout mice, and to mice with active Notch1 signaling. In each case, genetic cooperation was observed and characterized. Oncogenic PI3K cooperated with p53-loss and active Notch1 to decrease survival and alter tumor phenotype in distinct ways. Loss of PTEN cooperated with oncogenic PI3K to alter tumor type, decrease average age at end point, and increase the number of tumors per mouse. Overall, I have shown that Pik3caE545K and Pik3caH1047R are sufficient to induce mammary tumors, and that tumor characteristics differ with these mutations, and with cooperating genetic changes.

Identiferoai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/43368
Date11 December 2013
CreatorsAdams, Jessica
ContributorsEgan, Sean
Source SetsUniversity of Toronto
Languageen_ca
Detected LanguageEnglish
TypeThesis

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