Identification of Potential Therapeutic Mechanisms for HIP1 Inhibition in Breast Cancer
Final rept. 14 Apr 2004-13 Apr 2007
MICHIGAN UNIV REGENTS ANN ARBOR DIV OF RESEARCH DEVELOPMENT AND ADMINISTRATION
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The first hypothesis we tested in this grant is that HIP1 expression is necessary for breast tumorigenesis. The ongoing experiments show that HIP1 deficiency does indeed inhibit the formation of breast tumors. This result is similar to our work that demonstrated that HIP1 is necessary for prostate tumorigenesis Bradley et al., 2005 Ca Res. These HIP1 deficientMMTV-Myc experiments have taken an interesting turnas a few tumors have developed in the Hip1 deficient mice. To understand how these tumors might develop we have examined the tumors for unpredicted expression of HIP1 polypeptides. We have discovered the presence of a 105 kDa form of HIP1 slightly truncated from the 116 kDa wild type . Upon sequencing of Hip1 DNA and message from these cells, we determined that this 105 kDa form of HIP1 is the product of splicing of a cryptic U12-type AT-AC intron. This event results in the insertion of an AG dinucleotide between exons 2 and 6 and restoration of the original reading frame. Remarkably, this mutant protein retains its capacity to bind lipids, endocytic proteins and EGFR. The expression of this mutant form of HIP1 in breast cancer cells provides clues for future investigations into the contribution of HIP1 to the homeostasis of normal and neoplastic tissues as different stages of development Graves et al., 2007, submitted. We think that this discovery emphasize the value of how sequencing the transcript that is actually produced by an engineered knock-out allele can reveal novel types of molecular compensation in cancer cells at the level of splicing. These data also indicate that the expression of HIP1 is necessary for the survival of Myc-induced breast cancers. The second hypothesis we have been testing is that dysregulation of endocytosis of EGFR by HIP1 is a mechanism by which HIP1 promotes breast cancer evolution.
- Anatomy and Physiology
- Medicine and Medical Research