In this application we propose to study the role of a novel family of phorbol ester/diacylglycerol receptors, the chimaerins, on events regulating invasion and metastasis. The chimaerins have Rac-GAP activity, and therefore accelerate the hydrolysis rate of GTP from Rac. Rac is a member of the Ras superfamily of GTP-binding proteins which act as a downstream effector of Ras in malignant transformation. A major goal of the parent grant (R0-1) is to define the mechanisms of regulation of chimaerin activity and the role of these novel phorbol ester receptors in carcinogenesis. We have strong evidence that chimaerins inhibit malignant transformation induced by Rac. The studies proposed in this application are logical extension of those proposed in the parent grant~ The main goal of this proposal is to evaluate whether chimaerins play a role in the molecular mechanisms of metastasis. For the studies proposed here, we will use a mammary adenocarcinoma model, the FII3 cell line. Many aspects of the metastatic cascade, including adhesion to substrates interaction with the extracellular matrix, spreading, and production of metalloproteinases, have been characterized by the foreign collaborator in this cellular model. Three aspects of the metastatic cascade will be evaluated.
In Specific Aim 1 we will evaluate whether chimaerins affect the production of enzymes involved in metastasis, such as metalloproteinases and plasminogen activators.
In Specific Aim 2 we will evaluate the role of chimaerins in migration and invasion.
In Specific Aim 3 we will study the role of chimaerins in metastatic dissemination using in vivo models. As a result of this collaborative effort we expect to gain essential information on the biology of these novelphorbol ester receptors and their role in carcionogenesis.
