Bone and lung are the two most frequent sites of metastatic recurrence in breast cancer. In work supportedby this grant we selected organ-specific metastasis cell subpopulations from the breast carcinoma cell lineMDA-MB-231, and derived a bone metastasis gene expression signature (BoMS) and a lung metastasissignature (LMS). We functionally validated many of these genes as mediators of bone or lung metastasis.With W. Gerald and A. Olshen, we showed the ability of these signatures to predict site of relapse in cohortsof primary breast tumors. We are defining the functions that are fulfilled by these genes, including roles ofBoMS genes IL11 and OPN in osteoclast activation during osteolytic metastasis, and roles of LMS genesEpiregulin, COX2, MMP1 and MMP2 in tumor neovascularization and metastatic extravasation. With R.Benezra and H. Varmus we are defining the role of LMS gene ID1 in conferring tumor-initiating capacity tometastatic breast cancers of the basal subtype. Based on these insights, we have proposed with L. Nortonthe 'tumor self-seeding' hypothesis of how certain metastatic functions may underlie the association of largetumor size, rapid growth rate, and metastatic behavior often seen in clinical cancer. Additionally, we havedefined mechanisms that allow breast cancer cells to avert the tumor-suppressive action of TGFR. Usingmouse models developed under P01-CA94060, we demonstrated roles of the TGFIJ-Smad pathway inbreast cancer metastasis to lung and bone. These models and target genes provide relevant assay systemsto test the effectiveness of existing and novel drugs against breast cancer metastasis. Building on thisprogress, in the next grant period we are planning to identify new bone and lung metastasis genes usingprimary malignant cells from fresh pleural effusions (Aim 1). We will seek to define functional andtherapeutically relevant interactions between validated metastasis genes (Aim 2). We will identify clinicallyrelevant genes mediating the pro-metastatic action of TGFB in lung and bone (Aim 3). Furthermore, we willexperimentally test the 'tumor self-seeding' hypothesis (Aim 4). Built into each of these specific aims is thedevelopment and application of relevant assay systems to test the effectiveness of therapeutic agents understudy in the Program Project. In sum, we are proposing to continue on the pace of discovery in breastcancer metastasis that was initiated during the previous grant period by this cooperative research effort.
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