The objective of these studies is to understand the effects of loss of the tumor suppressor Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) in breast cancer, and the effects of PTEN functions on tyrosine kinase signaling. Aberrant activation of the phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequent molecular alterations in human cancer, most often by loss of expression or loss-of-function mutations in PTEN. PTEN acts as a lipid phosphatase downstream of PI3K to antagonize PI3K signaling, but PTEN protein phosphatase activity has tumor suppressive effects which remain unresolved. PTEN deficiency results in activation of receptor tyrosine kinases (RTKs) including insulin-like growth factor-I receptor (IGF-IR), insulin receptor (InsR), and ErbB3/HER3, implicating PTEN in the modulation of signaling both upstream and downstream of PI3K. I therefore hypothesize that 1) the tumor suppressive effects of PTEN protein phosphatase activity involve direct dephosphorylation of oncoproteins including RTKs, and 2) PTEN loss sensitizes cancer cells to RTK inhibition. Results in support of hypothesis #1 would suggest that loss of PTEN not only increases PI3K pathway signaling, but also increases oncogenic signaling through protein-directed pathways that remain to be defined. In this case, PI3K inhibition may be insufficient to block the growth of PTEN-deficient tumors. Results in support of hypothesis #2 would offer PTEN loss as a biomarker of a patient subpopulation likely to benefit from RTK-directed therapy. To test these hypotheses, I propose the following Specific Aims: 1) To determine whether loss of PTEN modulates IGF-I, insulin, and HER3 receptor signaling;2) To determine whether PTEN loss sensitizes to therapeutic inhibitors of IGF-IR, InsR, and HER3;3) To discover phosphoprotein substrates of PTEN and the global effects of PTEN protein phosphatase activity on tyrosine kinase signaling. Global profiling of PTEN protein substrates and the effects of PTEN loss on tyrosine kinase signaling will identify novel roles of PTEN, offer candidate phosphoproteins altered by PTEN loss, and reveal new connections between signaling pathways. IGF-IR is expressed in the majority of human breast cancers, and therapeutic IGF-IR inhibitors are being developed. Identification of the effects of PTEN loss on IGF-IR signaling and sensitivity to IGF-IR-targeted therapies will reveal novel functions of PTEN, and determine whether PTEN status is a biomarker of response to therapy. In turn, these collective findings will allow the optimization of therapies targeting the IGF-IR and PI3K pathways. The studies proposed herein will be carried out at the Vanderbilt-Ingram Cancer Center, with facilities and centers ideally suited for the molecular, genetic, proteomic, and live animal imaging analyses involved in this research. This institution also provides extensive didactic activities and career development opportunities to enhance the training of young investigators. The above studies will provide me with enhanced scientific training in an environment rich with collaborations and interdisciplinary research to promote growth and independence. My immediate career goal is the acquisition of an independent, tenure-track, assistant professor faculty position to establish my own laboratory and research team, with the long-term goal of establishing an extramurally-funded program in mechanism-based translational cancer research.
PTEN loss is one of the most common aberrations in human cancer. These studies will dissect the mechanism(s) by which PTEN modulates tyrosine kinase signaling and therapeutic response to anticancer agents. This information will guide the design, development, and application of targeted cancer therapies.
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