title: Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma.
abstract: HuR is a ubiquitously expressed mRNA-binding protein. Intracellular localization of HuR is predominantly nuclear, but it shuttles between the nucleus and the cytoplasm. In the cytoplasm it can stabilize certain transcripts. Because nucleocytoplasmic translocation of HuR is necessary for its activity, it was hypothesized that cytoplasmic HuR expression in cancer cells could be a prognostic marker. To test the significance of HuR in carcinogenesis of the breast, we have investigated HuR expression in a mouse mammary gland tumor model and from 133 invasive ductal breast carcinoma specimens. HuR expression was elevated in the cyclooxygenase-2 transgene-induced mouse mammary tumors, and its expression was predominantly cytoplasmic in the tumor cells. In the human carcinoma samples, high cytoplasmic immunoreactivity for HuR was found in 29% (38 of 133) of the cases. Cytoplasmic HuR expression associated with high grade (P = 0.0050) and tumor size over 2 cm (P = 0.0082). Five-year distant disease-free survival rate was 42% [95% confidence interval (95% CI), 26-58] in cytoplasm-high category and 84% (95% CI, 76-91) in cytoplasm-negative or -low category (P < 0.0001), and high cytoplasmic expression of HuR was an independent prognostic factor in a Cox multivariate model (relative risk 2.07; 95% CI, 1.05-4.07). Moreover, high cytoplasmic HuR immunopositivity was significantly associated with poor outcome in the subgroup of node-negative breast cancer in a univariate analysis (P < 0.0007). Our results show that high cytoplasmic HuR expression is associated with a poor histologic differentiation, large tumor size, and poor survival in ductal breast carcinoma. Thus, HuR is the first mRNA stability protein of which expression associates with poor outcome in breast cancer.
authors.affiliation: Department of Pathology, University of Helsinki, Helsinki, Finland.
authors.forename: Mira
authors.initials: M
authors.lastname: Heinonen
authors.forename: Petri
authors.initials: P
authors.lastname: Bono
authors.forename: Kirsi
authors.initials: K
authors.lastname: Narko
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Chang
authors.forename: Johan
authors.initials: J
authors.lastname: Lundin
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Henry
authors.initials: H
authors.lastname: Furneaux
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.forename: Caj
authors.initials: C
authors.lastname: Haglund
authors.forename: Ari
authors.initials: A
authors.lastname: Ristimäki
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000096:biosynthesis*
chemical_list: D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016601:RNA-Binding Proteins