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Role of PTP1B in breast cancer

Objective

In 2006 alone, an estimated 410,000 women will die from breast cancer worldwide. Improved understanding of how breast cancer arises and the factors that determine breast tumour biology are urgently needed to improve treatment options. Tyrosine phosphorylation is a reversible process, mediated by protein-tyrosine kinases and protein-tyrosine phosphatases (PTPs) that regulate critical cell signalling pathways. Abnormal tyrosine phosphorylation underlies various diseases of deregulated growth and differentiation, including cancer.

This proposal focuses on the phosphatase PTP1B, an established negative regulator of insulin and leptin signalling that is a leading target of therapy for diabetes and obesity. PTP1B has also been implicated in breast cancer, including as a negative regulator of the receptor tyrosine kinase HER2 signalling. Conversely, PTP1B over-expression is found in 40-70% of human breast cancer and correlates with HER2 positive tumours. Thus, these studies offer contradictory conclusions on whether PTP1B potentiates or antagonizes HER2-mediated transformation in vivo, a question that remains unanswered. My preliminary data reveal that PTP1B ablation protects mice from HER2-evoked mammary cancer. Therefore, PTP1B appears to be a required positive component of HER2-evoked transformation, in contrast with its negative role in other receptor systems.

My specific aims include:
1. to determine the biochemical and cellular mechanisms underlying the cancer promoting effects of PTP1B on HER2-evoked breast cancer;
2. to address whether PTP1B is a suitable target of breast cancer therapy;
3. to define the precise pathogenic effect of PTP1B over-expression. Based on my preliminary data, I hypothesize that PTP1B targets key downstream signalling molecules to potentiate HER2-mediated transformation in the breast epithelium.

Moreover, I predict that PTP1B will be required for tumour maintenance and may be a novel cancer therapy target.

Call for proposal

FP6-2004-MOBILITY-12
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Coordinator

NOVARTIS FORSCHNUNGSSTIFTUNG, ZWEIGNIEDERLASSUNG FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH
Address
Maulbeerstrasse 66
Basel
Switzerland