Tid1, CHIP and ErbB2 Interactions and Their Prognostic Implications for Breast Cancer Patients

• Main Authors: Chia-Ing Jan, 詹佳穎
• Other Authors: Jeng-Fan Lo
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/14367223353087499046

博士 === 國立陽明大學 === 臨床牙醫學研究所 === 99 === ErbB2 (HER2/neu) is overexpressed in about 25~30% of breast malignancies, and up-regulation of ErbB2 in breast cancer patients is associated with poor prognosis. It is known that carboxyl terminus of heat shock cognate 70 interacting protein (CHIP) efficiently down regulates ErbB2 in vitro. Human tumorous imaginal disc 1 (Tid1), a co-chaperone of heat shock protein 70 (Hsp70), also suppresses ErbB2 expression in breast cancer cell lines. However, the intracellular interaction among Tid1, CHIP, and ErbB2 remains elusive, and the utilization of Tid1 and CHIP as breast cancer biomarkers has never been proposed. Herein, we analyzed the expressions and correlations among Tid1, CHIP, and ErbB2 in a total of 183 breast cancer histology sections, including 30 fresh tissue specimens using immunohistochemistry (IHC) and immunoblotting assay. Computerized image analytic system was used for IHC scoring and determining relative immunoblot intensity. The immunohistochemical expression of Tid1 and CHIP are positively correlated with each other but are both inversely correlated to that of ErbB2. Odds ratio analyses showed that lower expression of Tid1 has a relative higher risk of unfavorable tumor grade, later pathological stage, larger tumor size, and microscopic features of a more malignant histology including: lymphovascular invasion, stromal inflammatory response, and tumor necrosis. Expression of CHIP displayed the similar characteristics. Further, expression of Tid1 and/or CHIP increases patients’ 10-year overall, and disease free survival rate. Empirically, we also demonstrated that Tid1, CHIP and ErbB2 interacted with each other through immunofluorescence or co-immunoprecipitation analyses. Functionally, Tid1 and CHIP acted synergistically to degrade ErbB2 in vitro. Conversely, Tid1 cannot compensate for the loss of proteolytic function noted in CHIP mutations for degradation of ErbB2. Overall, our data suggests that Tid1 and CHIP play pivotal roles in affecting levels of ErbB2 protein, and that both are significant prognostic indicators of breast cancer patient survival.