The cohort of heat shock proteins (HSP) induced by cell stress becomes expressed at high levels in a wide range of tumors and is closely associated with a poor prognosis and resistance to cancer therapy. In addition, hsp are often induced by cancer therapy and may thus participate in resistance pathways, increased HSP transcription in tumor cells is due to the transcription factor heat shock factor 1 (HSF1) and plays an essential role in tumorigenesis. We have determined that HSF1 is a potent represser of non-hsp genes in tumor cells in addition to its role as an activator of hsp gene transcription. We have recently shown that the mechanism of gene repression includes recruitment by HSF1 of the powerful NuRD co-repressor complex which contains metastasis associated protein 1 (MTA1) as a major organizing component. Elevated expression of HSF1 correlates with increased MTA1 levels in advanced breast cancer. In this proposal, we will examine the role of the HSF1 / MTA1 / NuRD complex in the mechanisms of gene repression by HSF1 and the role of HSF1 repression the development of a metastatic phenotype. We will investigate the hypothesis that this complex can be recruited by the HER2 proto-oncogene agonist heregulin and can repress estrogen-inducible transcription and thus lead to pro-metastatic changes by switching the pattern of gene expression.
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