Abstract
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. 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. 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. Our findings provide in vivo evidence that htid is a tissue independent and evolutionarily conserved suppressor of ErbB-2.
Highlights
Htid encoded proteins are physiological partners of a wide spectrum of molecules relevant to neoplastic transformation
Since the identification of an experimental in vivo model mimicking human breast tumors is of great interest to dissect the oncosuppressive activity of the tid gene at the molecular level, we investigated mammary malignancies in transgenic mice carrying the rat counterpart of HER-2/ neu
The expression of htid and HER-2 RNA is altered in human breast tumors The htid tumor suppressor gene encodes three splice forms - htid-L, htid-I and htid-S - generated by alternative splicing [1,7,13]
Summary
Htid encoded proteins are physiological partners of a wide spectrum of molecules relevant to neoplastic transformation. In the fly, defined recessive mutations have been shown to be oncogenic in cell lineages responsive to This is of interest since over expression of ErbB-2, often caused by gene amplification, characterizes 20-30% of human breast cancers being casually linked to an aggressive clinical course of these tumors [17] and a variable percentage of extra-mammary tumors [18]. These data are consistent with the biology of the EGFR family members mediating control of cellular responses such as proliferation, differentiation, survival and apoptosis, essential for the maintenance of the transformed and metastatic phenotype. As a result the amount-ratio among the diverse htid forms and the HER2 transcript changes drastically
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