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Principal Investigator: Dr. Bendicht Pauli
Contact Information: E-mail: bup1@cornell.edu - Phone: 607-253-3343
Sponsor: Breast Cancer Coalition of Rochester
Grant Number: N/A
Title: Fibronectin and its Polymers in Breast Cancer Metastasis
Annual Direct Cost: $46,729
Project Period: 02/01/06-01/31/07
Lay Abstract: The "seed and soil" theory of metastasis entails that cancer cells (the seeds)
colonize only those secondary organs (the soil) that are able to support new tumor growth.
One determining factor of this concept is the ability of blood-borne cancer cells to recognize distinct endothelial cell surface molecules and used them as docking sites. An adhesion principle that facilitates colonization of the lungs has been discovered in a rat breast cancer model in my laboratory. It consists of endothelial cell dipeptidyl peptidase IV (DPPIV) and tumor cell surface associated fibronectin (Fn) organized into large, globular polymers (polyFn). The present proposal is designed to gain a better understanding of the mechanisms by which breast cancer cell assemble polyFn and to introduce a mouse model, in which the mammary fat pad is "humanized," i.e., human stromal cells are used to repopulate the area of the excised mouse fat pad prior to injection of spheriods of a mixture of human stromal and cancer cells. This "xenograft model" has the advantage that we can evaluate the contribution of a gene of interest (e.g., Fn) to breast cancer progression (e.g., metastasis) in a situation that more closely mimics the human. In the first aim, we have already established that polyFn accumulates on lung metastatic breast cancer cells as soon as they enter the blood and that this process is regulated by protein kinase C delta (PKCd). In order to identify molecules that cooperate with PKCd in polyFn assembly, we use a relatively new biochemical method, which allows the direct sequence identification of a coprecipitated PKCd-partner (Mass Spectrometry). The goal of this part of our study is to identify potential targets for future therapeutic intervention in metastasis. In the second aim, the xenograft model is used to evaluate a lung-metastatic, Fn-positive human breast
cancer cell line. The performance of this cell line will be compared with the same cells, but whose Fn has been depleted by siRNA knockdown. We will examine whether the Fn effect is restricted to the recognized polyFN/DPPIV docking mechanism, or whether it also affects other steps of the metastatic cascade, e.g., invasiveness, susceptibility to apoptosis. Together the planned studies will give us an overview of the role of Fn in metastasis, and provide long overdue explanations for the previously recognized prometastatic role of Fn.
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