Defining the physiological function of the plasminogen receptor, S100A10 (p11).

It is now accepted that inflammation is necessary to maintain and promote the growth of the benign breast cancer cells within the tumor and also to teach these benign cancer cells how spread and become metastatic and therefore lethal. One of the key players in the inflammatory response, blood cells called macrophages, must chew their way through the tissue material that surrounds the tumor in order to reach the cancer cells in the tumor. My laboratory has shown, in a mouse model of lung cancer, that macrophages use a protein on their cell surface called S100A10 to allow them to chew through the tissue barriers and reach the tumor. If macrophages are prevented from expressing S100A10, they cannot chew through tissue barriers and and do not reach the tumor site and as a result tumor growth is reduced by as much as 90%. We plan to use the PyMT mouse model of breast cancer to determine if macrophages use S100A10 to regulate their chewing activity in order to allow them to reach the breast tumor site and promote tumor and metastatic growth. Similarly, we will also test the possibility that the cancer cells themselves may also use S100A10 to chew through the tissue barriers and metastasize to the lungs. The PyMT mouse is an exceptional model system because these mice develop breast tumors and lethal metastases in a similar way to human breast cancer. Thus by crossing the PyMT mouse with our S100A10-null mouse, we will produce mice that develop breast cancer but whose macrophages and cancer cells cannot express S100A10. By comparing the rate of growth of the breast tumors and the development of metastatic foci between PyMT mice that express and others that cannot express S100A10, we will determine if S100A10 plays an important role in breast cancer. If S100A10 does play a role in tumor growth and/or metastasis it could represent an important target for development of a new class of drugs that block the function of this protein.