Author

Harold Kim

Date of Award

2003

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. William J. Muller

Abstract

Breast cancer research has focused on a number of key molecular events suspected to play critical roles in the establishment and progression of the human disease. For example, the c-ErbB2 receptor is amplified or overexpressed in approximately 30% of all human breast cancer cases, its overexpression inversely correlating with a positive patient prognosis. In addition, the estrogen receptor is a key marker in assessing patient prognosis, the progression of the disease state, and is by far the most utilized target to treat breast cancer with approximately 100 million hours of clinical experience with the antiestrogen, Tamoxifen. While these two receptor systems play critical roles in breast cancer progression, the activation of downstream signaling pathways and its consequences on cellular function are unclear. Interestingly, the c-Src tyrosine kinase has been identified to play a role in the modulation of both the c-ErbB2/Neu and the estrogen receptor. Here I will describe a role for c-Src in modulating c-ErbB2/Neu receptor activation and its associated ability to transform at the molecular level, as well as a role for c-Src in estrogen receptor mediated mammary gland development. Significantly, the association of c-Src to the c-ErbB2/Neu receptor plays an important role in the direct and specific activation of the receptor. Furthermore, the loss of c-Src within the mammary gland negatively impact its development, this delay being mediated via the estrogen receptor. Taken together, these studies demonstrate the importance of c-Src in two receptor systems that have been heavily implicated in development and disease, the estrogen receptor and the c-ErbB2/Neu. In both cases, c-Src plays a critical role in receptor activation, coordinating downstream events impinging on reproductive development and in mammary gland transformation. The understanding of the molecular crosstalk between these receptor systems within the mammary gland may provide insight into potential translational therapies in clinical research.

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