The Type I Insulin-like Growth Factor Receptor (IGF-IR) clearly plays a critical role in breast tumorigenesis through its capacity to facilitate malignant transformation, promote cell proliferation, and protect malignant cells from apoptosis. The human IGF-IR mRNA contains an extraordinarily long (1,038 nucleotides) leader sequence (5'-untranslated RNA, 5'-UTR), which functions as the equivalent of a """"""""promoter"""""""" at the RNA level. We have identified three regulatory proteins (HuR, TIAR, hnRNP C) that bind in a sequence-specific manner to the IGF-IR 5'-UTR and appear to control the efficiency with which the IGF1R mRNA is translated into protein. We hypothesize that alterations in the dynamic interactions between these RNA-binding proteins and the 5'-untranslated sequence of the IGF-IR transcript may be responsible for IGF-IR overexpression in a proportion of human breast tumors, and ultimately contribute to the molecular pathogenesis of this disease. Indeed we have found a marked increase in IGF-IR translational efficiency in association with significant alterations in the activities of these RNA-binding proteins in the human breast carcinoma cell line T47D, which overexpresses IGF-IR. In addition, we propose to test the potential therapeutic utility of the isolated IGF-IR 5'-untranslated RNA, functioning as a dominant negative regulatory RNA, to specifically counteract IGF-IR overexpression and reverse the associated adverse phenotypic consequences in human breast cancer cells. We have established that such a strategy can be used to induce dramatic, favorable phenotypic alterations, including mitotic cell death and loss of tumorigenicity.
The Specific Aims are: 1. Establish the function of the RNA-binding proteins TIAR and hnRNP C in the regulation of IGFIR expression at the translational level. 2. Assay primary human breast tumor specimens for the activities of sequence, specific translation-regulatory proteins binding the 5'-untranslated region of the human IGFIR transcript (including HuR, TIAR, and hnRNP C), and correlate changes in activities of these RNA-binding proteins with IGF-IR overexpression and the malignant phenotype. 3. Ectopically express the isolated IGFIR 5'-untranslated RNA sequence in human breast cancer cells, assess the potential of this non-coding RNA sequence to modulate IGF1R expression, and consequently limit proliferative capacity, enhance apoptotic susceptibility, and reverse tumorigenicity of human breast cancer cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Perry, Mary Ellen
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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