Grant: Operating Grant

My lab investigates genetic mechanisms that contribute to cancer in the mammary gland or the breast. One of the ways we examine these mechanisms is by using a mutant mouse that harbors a small mutation in a gene called Patched-1. Patched-1 is part of a signaling network that controls the formation of many tissues during embryogenesis. This same signaling network is also involved in the formation of a number of cancers, including breast cancer. We found that the small mutation in Patched-1 prevented the development of the mammary gland of mice (breast in humans) during puberty. Interestingly, we also found that this same mutation could prevent the formation of tumors in mice that carried another cancer-causing gene, called ErbB2, that is involved in breast cancer in humans. However, a different cancer-causing gene, called Wnt-1, was still able to cause abnormal growth in the mouse mammary gland despite the presence of the mutation in Patched-1. Taken together, our studies have defined a novel network of interacting molecules that play an important role in development of the breast or mammary gland. We hypothesize that the network involving Patched-1 effect the ability of another gene mutated in a large number of human breast cancers, called p110-alpha, to produce tumors. To test this hypothesis, we will breed mice that have mutations in the pathway controlled by Patched-1 and the pathway involving p110-alpha, in order to understand how these two pathways interact and control the formation of breast tumors. We will then determine if drugs that specifically target parts of these same two pathways control the growth of tumors. Our experiments will provide a powerful system to understand how two signaling networks cooperate to cause breast cancer. Our models of breast cancer will then be used to show how specific combinations of drugs can stop the formation or growth of the tumors arising due to mutations in the pathways controlled by Patched-1 and p110-alpha.