Identification of Potential Therapeutic Mechanisms for HIP1 Inhibition in Breast Cancer
Annual rept. 14 Apr 2005-13 Apr 2006
MICHIGAN UNIV ANN ARBOR
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The first hypothesis we are testing is that HIP1 expression is necessary for breast tumorigenesis. We have successfully generated a cohort of breast cancer prone mice MMTV-Myc that are deficient n20 or replete for HIP1 n20. The ongoing experiments show that HIP1 deficiency inhibits 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 HIPI deficientMMTV-Myc experiments have taken an interesting turn this year. Essenfially we have analyzed the rare tumors that develop in the MMTV-MycHip1 knockout mice and found that cells derived from these tumors but not the normal tissues from the same mouse express a mutant form of HIP1. We think that this is a way for the cells to adapt to the original targeted loss of function mutation in the Hip1 gene. These data indicate that the expression of HIP1 is completely necessary for the survival of Myc-induced breast cancers. Our plan is to identify the sequence of the mutant forms in hopes of discovering areas of the HIP1 sequence to target for small molecule inhibition. 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. Indeed we have found that HIP1 overexpression inhibits the degradation the EGFR Hyun et al. 2004 J Biol Chem. Showing that HIP1 is necessary for breast cancer progression and modulates key growth factor receptors involved in breast cancer fuels the idea that HIP1 inhibition has excellent therapeutic potential. We will continue to explore the activity of distinct regions of HIP1 to discover inhibitors for use in the treatment of breast cancer.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research