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Development of an insturmal method to evaluate insulin receptors and insulin-like growth factor-1 receptors homodimers and hybrid receptors in breast cancer

Date

2016

Authors

Shebani, Karima Ali, author
Roess, Deborah A., advisor
Roess, Deborah A., committee member
Barisas, George B., committee member
Miller, Charles W., committee member

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Abstract

Breast cancer is a major public health problem in the United States and many other parts of the world. It is the second most common cancer and second leading cause of cancer death among women in the US. Insulin receptors (IR) and insulin-like growth factor-1 receptors (IGF1R) are found in normal mammary gland cells where they are involved in normal development and differentiation of these cells. There is substantial clinical, epidemiological, and experimental evidence indicating that these receptors are also involved in initiation and progression of neoplasia of mammary gland cells. IR and IGF1R numbers are increased in breast cancers and raise the possibility that IR and IGF1R may have roles in the biology of these tumors. In this project, we have developed new methods to evaluate the presence of IR homodimers and hybrid receptors formed from IR and IGF1R monomers. In initial experiments we have used three cell lines of CHO that stably express IR-GFP. Using flow cytometry, we found that low expressing cells had ~ 62,000receptors/cell, moderately expressing cells had ~ 130,000receptors/cell, and high expressing cells had ~ 205,000 receptors/cell. We then used homo-transfer fluorescence resonance energy transfer (homo-FRET) methods to evaluate possible interactions between IR monomers in the IR homodimer or IR and IGF1R subunits in hybrid receptors. Our results suggest that IR exists as an apparent monomer in cells expressing low numbers of IR-GFP. In cell lines highly expressing IR-GFP, there are minimally dimers and higher order receptor oligomers present on the plasma membrane. These results suggest that when IR is highly expressed, as in the case in many breast cancers, the receptor is likely to be found as a IR homodimer rather than as a hybrid IR-IGF1R receptor. Further studies beyond the scope of this project will evaluate the effects of IGF1R expression on the formation of IR homodimers.

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