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Principal Investigator: Dr. Tamas Nagy
Mentor: Dr. Jun-Lin Guan
Contact Information: E-mail: tn35@cornell.edu - Phone: 3-3613
Sponsor: Department of Defense - Breast Cancer Research Program
Grant Number: W81XWH-04-1-0400
Title: Mammary Carcinogenesis Using a Transgenic Mouse Model
Annual Direct Cost: $27,778
Project Period: 3/26/04-3/25/07
The development of human breast cancer is intimately intertwined with certain cell surface molecules, the integrins, which anchor cells to the outside matrix and bidirectionally transmit information between cells and their surroundings. A molecule called the focal adhesion kinase (FAK) is a pivotal player in this flow of information. Recent reports demonstrate enhanced FAK activity in breast cancer. Work in our laboratory resulted in identification of a novel protein, FIP200 (FAK-family Interacting Protein of 200 kDa) that inhibits FAK activity. Among other effects, FIP200 can slow down cell migratory activity and the process of cell division, both of which can be associated with overactive FAK. We have created a transgenic mouse line in which regulated overexpression (production in larger than normal quantities) of FIP200 can be targeted to the mammary gland. We are currently testing these animals for the proper functioning of the system. FIP200 --through its inhibition of FAK-- could significantly inhibit the development of mammary cancer in our transgenic system.
The goal of our proposed study is to further test and later use our transgenic mice in experiments that focus on the maturation of the mammary gland in late pregnancy (when rapid cell division takes place). Additionally we will use these mice in experiments in which mammary cancer is induced in specific ways to see whether FIP200 can slow down the development and progression of the disease.
We intend to use these transgenic mice in different experiments that would elucidate the exact role of FIP200 in the mammary gland both in health and in disease. Data from our and other laboratories indicate that FIP200 might interfere with the normal maturation of the mammary gland in late pregnancy. In the first set of experiments we will investigate if the overexpressed FIP200 could indeed inhibit mammary gland maturation during late pregnancy. In the second set of experiments mammary gland tumors will be induced by feeding the mice with a specific chemical and tumor size and number and FAK activation will be determined and compared to a control group of mice. Investigations will also focus on the activity and behavior of certain proteins that can inhibit tumor formation (so called tumor suppressors). In the third set of experiments our transgenic mice will be mated with another transgenic line (that characteristically develops mammary tumors early in life). We will determine the tumor size and number and FAK activation in the offsprings. Additional experiments will be conducted to follow the behavior of certain tumor suppressors in the offsprings. Our proposal deals with the development of a new transgenic mouse model to study human breast cancer. Work in our laboratory mostly concentrated on the behavior of FIP200 in cell culture systems. In order to learn more about the possible role of FIP200 in human breast cancer, we need to continue the cell culture studies, but we have to conduct animal experimentation simultaneously. Our proposed investigations are aimed at understanding the behavior of an important cellular protein that has been shown to inhibit cellular behaviors that are hallmarks of the development and progression of cancer. Our approach, albeit too basic for tangible clinical applications, could produce important interim results that can have clinical applications. One possible clinical application is to screen biopsies of human mammary cancers for the presence of FIP200 to see if that could be correlated with prognosis. Another possible clinical application would be to design small proteins (peptides) based on the structure of FIP200 that can effectively inhibit the malignant process. Another, although quite distant, clinical application would be to use FIP200 in gene therapy.
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