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Author

Niki Sharan

Date of Award

9-2004

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Professor William J. Muller

Abstract

Overexpression of the Neu/ErbB-2 receptor tyrosine kinase is implicated in the genesis of human breast cancer. Previous studies have observed elevated levels of endogenous ErbB3 protein in Neu-induced tumors. Although it has been suggested that the aberrant co-expression of Neu and ErbB3 may play a critical role in the induction of human breast tumors, the biological significance and the molecular mechanism of ErbB3 regulation during Neu-mediated tumorigenesis remains unclear. The results of this thesis demonstrate that the ability of ErbB3 to be constitutively phosphorylated and to regulate cell cycle progression through the activation of the PI-3K/mTOR pathway fully depends on the activity of Neu. Both PI-3K and mTOR in turn are involved in sustaining high levels of ErbB3 protein by increasing its stability. A mutant of ErbB3 unable to recruit and activate PI-3K (ErbB3-6F), blocks Neu-induced transformation, disrupts the mTOR/4EBP1 pathway and leads to apoptotic cell death. This strongly suggests that ErbB3 's role in these tumors is to provide cell survival signals by recruiting the p85 regulatory unit of PI-3K and coupling overexpressed Neu to the PI-3K/mTOR/4EBPl pathway. This thesis further demonstrates that the mTOR inhibitor rapamycin, delays the onset and inhibits the growth of Neu-induced mammary tumors in transgenic mice. The rapamycin-induced tumor inhibition correlates with downregulation of ErbB3, S6K, 4EBP1 and cyelin D1. I also show that the ErbB3-6F mutant exhibits antitumor activity in vivo by preventing tumor growth and facilitating tumor regression. Therefore, the antitumor activity of the rapamycin analogue, CCI-779 in human breast cancer may be mediated, in part, through the inactivation of ErbB3 thereby inhibiting the critical cell survival signals necessary for transformation. Taken together these results strongly suggest that Neu requires ErbB3 to drive mammary transformation and that the ErbB2/ErbB3 heterodimer may function as an oncogenic unit to recruit distinct yet complimentary signaling pathways that cooperate during mammary tumor progression. The results of this thesis provide a molecular basis for the selective targeting of the ErbB3/PI-3K/mTOR signaling pathway in the treatment of HER2-mediated human breast malignancies in which HER3 is overexpressed.

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