title: Tid1, CHIP and ErbB2 interactions and their prognostic implications for breast cancer patients.
abstract: 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 the carboxyl terminus of heat shock cognate 70 interacting protein (CHIP) efficiently down-regulates ErbB2 in vitro. Human tumourous imaginal disc 1 (Tid1, DnaJa3), a co-chaperone of heat shock protein 70 (Hsp70), also suppresses ErbB2 expression in breast cancer cell lines. However, the intracellular interactions among Tid1, CHIP, and ErbB2 remain elusive, and the utilization of Tid1 and CHIP as breast cancer biomarkers has never been proposed. Herein, we analysed the expression 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. A computerized image analysis system was used for IHC scoring and determining relative immunoblot intensity. The immunohistochemical expression of Tid1 and CHIP were positively correlated with each other but were both inversely correlated to that of ErbB2. Odds ratio analyses showed that lower expression of Tid1 has a relatively higher risk of unfavourable tumour grade, later pathological stage, larger tumour size, and microscopic features of a more malignant histology including lymphovascular invasion, stromal inflammatory response, and tumour necrosis. Expression of CHIP displayed similar characteristics. Furthermore, 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 suggest that Tid1 and CHIP play pivotal roles in affecting the levels of ErbB2 protein, and that both are significant prognostic indicators of breast cancer patient survival.
authors.affiliation: Department of Dentistry, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Ing
authors.initials: CI
authors.lastname: Jan
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Horng-Jyr
authors.initials: HJ
authors.lastname: Harn
authors.forename: Shin
authors.initials: S
authors.lastname: Nieh
authors.forename: Herng-Sheng
authors.initials: HS
authors.lastname: Lee
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Lou
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Wu
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chen
authors.forename: Chi-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Fei-Na
authors.initials: FN
authors.lastname: Chen
authors.forename: Jeng-Fan
authors.initials: JF
authors.lastname: Lo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D004812:Epidemiologic Methods; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D050956:HSP40 Heat-Shock Proteins; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D044767:Ubiquitin-Protein Ligases; C120664:DNAJA3 protein, human; C467728:STUB1 protein, human; C508053:ERBB2 protein, human