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- Characterization of novel JAK inhibitors. A number of human malignancies express the TEL-JAK fusion protein described above, which induces the persistent dimerization and constitutive activation of JAK2. The JAK2 inhibitor (AG490) first used against leukemia cells in which the kinase is constitutively active, has more recently been found to induce growth arrest or apoptosis in many tumor-derived cell lines including breast and prostate cancers, suggesting that this kinase is important in a variety of cancers. We have been developing new JAK inhibitors in collaboration with Bill Bornmann and are in the process of testing them both in vitro and in vivo.
- Mechanism(s) of Transformation by Activated STAT3 in Breast and Prostate Cancer. We have successfully introduced activated STAT3 (STAT3-C) into a number of immortalized epithelial cell lines resulting in de-novo transformation as characterized by growth in soft agar and in nude mice. By Affymetrix Chip analysis, we have identified a number of potential target genes of activated STAT3. We have recently determined that one of these targets, MMP-9 is required for STAT3-C mediated transformation. We are in the process of characterizing other target genes, including Cortactin, Psoriasin (and others), and their role in STAT3-mediated growth and transformation.
- Activated STAT3 and Epithelial Morphogenesis. In collaboration with Joan Brugge at Harvard, we have examined the effects of activated STAT3 on morphogenesis of breast epithelial cells. Specifically, STAT3-C expressing MCF 10A cells grow as filled-in structures in contrast to vector control expressing MCF 10A cells. Furthermore, oncogenes (including her2neu and src) when introduced into MCF10A cells results in the activation of endogenous STAT3 and abnormal morphogenic growth in the presence of matrigel. We are interested in determining the mechanisms by which activated STAT3 leads to abnormal growth in 3D.
- Constitutively activated STAT3 (STAT3-C) in murine models of breast carcinogenesis. We have generated transgenic animals expressing inducible STAT3-C targeted to breast tissue. We are now in the process of examining the effect of this protein on breast development and its potential role in tumorigenesis.
- Determine the distribution and abundance of activated STAT3 in primary breast cancer specimens and correlate with expression of known indicators of tumor progression, aggressiveness, and differentiation. In addition, we will begin to characterize the potential regulators of STAT3 activation in these tissue specimens.
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