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    Awarded Grants
    Stat5 a Novel Therapeutic Protein for Breast Cancer Invasion and Mesenchymal Transition Regulation

    Scientific Abstract:
    Stat5 a novel therapeutic protein for breast cancer invasion and mesenchymal transition regulation. i. Background: Epithelial-to-mesenchymal dedifferentiation is required for invasion of individual tumor cells and establishment of metastatic cell colonies. To this end, we plan to restore loss of a key pathway that drives breast epithelial differentiation, with the goal of reversing the epithelial-to-mesenchymal dedifferentiation. Accumulating data based on breast cancer models in rodents assumed that the central signaling axis used by PRL-Jak2 tyrosine kinase-Stat5 transcription factor pathway, contributes positively to tumor promoting effect of PRL. However, as a radical departure from this view of PRL as a tumor promoter, we now propose that PRL through its central signaling axis, Jak2-Stat5, is a central suppressor of breast cancer invasion and metastasis. ii. The rationale behind our novel concept centers on compelling and unexpected observations: First, Stat5 is constitutively active in normal human breast epithelium, and that this activation is lost during metastatic breast tumor progression. Second, loss of Stat5 activation in the primary tumor of patients with lymph node-negative breast cancer is associated with an eight-fold increased risk of latent, residual disease and subsequent death from breast cancer. Third, gene delivery of Stat5 and Jak2 into a poorly differentiated breast cancer cell line synergized to promote epithelial differentiation and inhibited invasive characteristics. iii. Objectives/Methods: Our working hypothesis is that the activated Stat5 maintains homotypic adhesion of a majority of human breast cancer cells, and promotes mesenchymal-to-epithelial differentiation, with the direct potential of turning progressive and metastatic breast cancer into a chronic but stable condition. Stat5 activity will be experimentally manipulated in human breast cancer cells for in vitro studies of invasion and in vivo studies of peritumoral stromal invasion, using a series of new and highly specialized molecular tools and techniques that we have generated, especially our established adenoviral delivery systems for proof-of-principle preclinical testing. i.v. Relevance: The work is important because it is expected to have mechanistically tested the novel invasion-suppressive role of Stat5 activation in human breast cancer on reversing the epithelial-to-mesenchymal dedifferentiation, which could lead to improved diagnostic classification of breast cancer and to more effective and individualized therapeutic options.

    Lay Abstract:
    Stat5 a novel therapeutic protein for breast cancer invasion and mesenchymal transition regulation. Epithelium-to-mesenchyme transition (EMT) is thought to play a fundamental role during the early steps of invasion and metastasis of carcinoma cells. This EMT allows cells to dissociate from the epithelial tissue from which they originate and to migrate freely. The coordinated changes in cell morphology, associated with the induction of cell motility and the disruption of adhesion junctions, are the consequence of a signaling cascade emanating from the cell membrane and leading to changes in gene expression. The novel findings from our laboratory introduces active transcription factor Stat5 as a new suppressor for breast cancer invasion and metastasis by maintaining breast epithelial cell differentiation, and perhaps directly inhibiting epithelial-mesenchymal transition needed for extratumoral invasion. Our target is to identify mechanistic regulatory function of Stat5 in the early molecular changes of EMT that promote invasion potential and metastatic progression of breast cancer. This study will have a great impact on developing of better strategies for prevention of metastatic spread and identifying new therapeutic intervention of advanced breast cancer. Stat5 activity will be experimentally manipulated in human breast cancer cells for in vitro studies of invasion and in vivo studies of peritumoral stromal invasion, using series of highly specialized molecular tools and techniques that we have generated for that purpose. This strategy will allow effective experimental regulation of Stat5 activity in human breast tumors at various stages of progression. As an outcome of the proposed investigations, we expect to understand the mechanistic regulatory role of Stat5 on EMT and invasion potential in breast cancer, which will offer new perspectives for designing therapies for the treatment of metastatic cancers of epithelial origin.