In vivo evidence of htid suppressive activity on ErbB-2 in breast cancers over expressing the receptor.

BACKGROUND: Htid encoded proteins are physiological partners of a wide spectrum of molecules relevant to neoplastic transformation. One of the molecular ligands of the cytosolic hTid-L and hTid-I forms is the ErbB-2 receptor variably over expressed in diverse solid tumors. Altered ErbB-2 signalling is associated with an unfavourable prognosis in about 30% of human breast malignancies. METHODS: We evaluated htid and HER-2 expression by quantitative real time PCR in tumors of different TNMG status and by immunohistochemistry in a cohort of breast tumors of the Luminal A, B, HER-2 and triple negative subtype. RESULTS: The RT-PCR analysis revealed that aberrant expression of all three htid forms correlates with malignant transformation. Furthermore, elevated hTid-L expression can be associated with less aggressive tumors. The immunohistochemical testing revealed that tumors of the luminal A subtype are characterized by a high level of htid (81%). In contrast htid expression is significantly lower in tumors of the Luminal B (20%) and HER-2 (18%) subtype over expressing the receptor and in the triple negative (40%) more aggressive malignancies. A statistically significant inverse correlation between htid and ErbB-2 expression was found in human breast (p < 0,0001) and non-mammary tumors (p < 0,007), and in transgenic mice carrying the rat HER-2/neu oncogene. CONCLUSIONS: Our findings provide in vivo evidence that htid is a tissue independent and evolutionarily conserved suppressor of ErbB-2.

Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor.

Recently, we identified htid-1, the human counterpart of the Drosophila tumor suppressor gene lethal(2)tumorous imaginal discs [l(2)tid], as a direct molecular ligand of the adenomatous polyposis coli (APC) tumor suppressor. The gene encodes three cytosolic (Tid50, Tid48 and Tid46) and three mitochondrial (Tid43, Tid40 and Tid38) proteins. In the colorectal epithelium the cytosolic forms hTid50/hTid48 interact under physiological conditions with the N-terminal region of APC. This complex which associates with additional proteins such as Hsp70, Hsc70, Actin, Dvl and Axin defines a novel physiological state of APC unrelated to beta-catenin degradation. Here we show that the expression of the genes htid-1 and APC was altered in colorectal tumors. These changes concerned both the localization and the expression level of all three htid-1 splice variants and of APC. Furthermore, we showed that the protein products of the two tumor suppressors co-localized in the basal and apical region of normal colon epithelia and that loss of differentiation capacity of colorectal cancers correlated with a shift in their expression patterns from compartmentalized to diffuse cytoplasmic. These findings support our hypothesis that the building of the multi-component complex mentioned above is associated with the maintenance of the polarity of cells and tissues. In addition, we provide evidence that colon cancer progression correlates with up-regulation of htid-1 and its ligand Hsp70. Since the Tid proteins are members of the DnaJ-like protein family, an essential component of the Hsp70/Hsc70 chaperone machinery, our findings describe a novel, causal link between the function of chaperone machines, APC-mediated Wg/Wnt signaling and tumor development.