GSBS Dissertations and Theses

Approval Date

3-29-2012

Document Type

Doctoral Dissertation

Department

Graduate School of Biomedical Sciences, Program in Cancer Biology, MD/PhD Program

Subjects

Dissertations, UMMS; Breast Neoplasms; Receptors, Somatomedin; Insulin Receptor Substrate Proteins; Protein Transport; Neoplasm Invasiveness

Abstract

The insulin-like growth factor-1 receptor (IGF-1R) and many of its downstream signaling components have long been implicated in tumor progression and resistance to therapy. The insulin receptor substrate-1 (IRS-1) and IRS-2 adaptor proteins are two of the major downstream signaling intermediates of the IGF-1R. Despite their considerable homology, previous work in our lab and others has shown that IRS-1 and IRS-2 play divergent roles in breast cancer cells. Signaling through IRS-1 promotes cell proliferation, whereas signaling through IRS-2 promotes cell motility and invasion, as well as glycolysis. Moreover, using a mouse model of mammary tumorigenesis, our lab demonstrated that IRS-2 acts as a positive regulator of metastasis, while IRS-1 cannot compensate for this function.

The focus of my thesis research is to understand how IRS-2, but not IRS-1, promotes breast carcinoma cell invasion and metabolism to support metastasis. In preliminary studies, I have found that IRS-1 and IRS-2 exhibit different expression patterns in both cell lines and human tumors with correlations to patient survival, which provides a potential mechanism for their distinct functions. The localization of IRS-1 and IRS-2 within separate intracellular compartments would determine their access to downstream effectors and substrates, and this would result in unique cellular outcomes. Specifically, I have observed that IRS-2, but not IRS-1, co-localizes with microtubules in breast carcinoma cell lines with implications for signaling through AKT and mTORC2. The goal of this research is to determine how the localization of IRS-2 contributes to its regulation of breast cancer progression and response to therapy and how this information could be used to better predict patient outcomes.

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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