Toward a transcription therapy for breast cancer. The development of breast cancer is the consequence of uncontrolled growth of breast-ductal epithelial cells. Estrogen hormones, particularly 17beta-estradiol (E2), within the context of interrelated growth signaling pathways play critical roles for the initiation and development of breast cancer. The E2 signaling is primarily conveyed by the transcription factors estrogen receptors (ERs) alpha and beta. E2-ER mediates genomic and non-genomic events that orchestrate cell proliferation, differentiation and death. The interaction of E2-ER with specific DNA sequences, estrogen responsive elements (EREs), constitutes one primary genomic signaling. The E2-ER-mediated events are also affected by intracellular signaling pathways that cross-talk with ER and mutant ERs. Approaches to reduce/ablate the circulating E2 or to alter/prevent ER function constitute the current experimental and therapeutic modalities. Perturbations of the estrogen/ER environment are initially successful in the remission of established tumors. However, many breast tumors are not responsive or eventually develop resistance to these therapies. The absence/loss of ER expression, aberrant signaling pathways and/or variant ERs are thought to circumvent the need for ligand-ER mediated events rendering such approaches ineffective. We sought to overcome the limitations imposed by ligand, dimerization and ER-subtype in E2 signaling by specifically regulating the ERE-driven gene network. The modular nature of ER allowed us to design a monomeric ERE binding module by co-joining two DNA binding domains with the hinge domain (CDC). Integration into this CDC module of strong activation domains from other transcription factors generated constitutive ERE binding activators that specifically induced ERE-driven gene expression independent of ligand, dimerization, ER-subtype, and cell-context. We predict that the CDC module may also be used to generate potent ERE binding repressers. To effectively assess the impact of ERE binding transregulators on gene expression and subsequent alterations in cell phenotypes in vitro and in vivo, we propose to establish an adenoviral gene delivery system. Using this system, we will also identify the ERE-driven genes by a gene array approach. We anticipate that findings will be critical for the identification of new therapeutic targets, the development of prognostic tools and of a novel """"""""transcription therapy"""""""" for breast cancer. ? ? ?
