This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long term objective of our laboratory is to identify a key molecule that is sufficient to induce and sustain the phenotypes of normal epithelium in cancer cells. This project is innovative because it explores an intrinsic therapeutic pathway leading to the suppression of carcinoma progression through reestablishing normal phenotypes of epithelial cells. Dysfunctional epithelialization is characterized by loss of contact inhibition, gain of anchorage-independence, and inactivation of anoikis, a mode of cell death specifically induced after cell detachment from substratum. These phenotypes are all among the hallmarks of malignant carcinomas derived from transformed epithelial cells. We propose to test the hypothesis that BIN1, a nucleo-cytoplasmic adaptor protein that was identified originally as a c-MYC oncoprotein?interacting tumor suppressor, induces and sustains the epithelial-like phenotypes through inhibiting c-MYC. To test this hypothesis, we aim to 1) investigate whether c-MYC inhibition is necessary and sufficient for the BIN1-mediated epithelialization, 2) identify the BIN1 effectors that mediate contact inhibition and/or anoikis in malignant carcinoma cells, and 3) establish the upstream oncogenic pathways that enable the protection of carcinoma cells from BIN1-mediated epithelialization. To achieve the first aim, we will investigate the biological effects of activation and inactivation of the c-MYC oncoprotein on epithelial phenotypes in the presence of BIN1. To define the downstream signaling mechanism by which BIN1 sustains epithelial phenotypes in metastatic cancer cells, we will identify BIN1 effector molecules that are essential for mediating BIN1-dependent epithelialization. We previously reported that the abundance of BIN1 is significantly reduced or undetectable in malignant carcinoma cells. However, little or no human BIN1 gene deletion or translocation was evident in BIN1-deficient cancer cells, suggesting that oncogenic pressures might reduce the amounts of BIN1 mRNA or protein. Consistently, our preliminary results demonstrate that receptor-type tyrosine kinase oncoproteins, such as EGFR, negatively regulate BIN1 levels. Completion of this project will identify epithelium-associated BIN1 signaling pathways. This knowledge will be significant, as it may provide a unique therapeutic intervention by which metastatic potential of carcinoma cells may be eliminated by increasing BIN1 levels.
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