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. (Cancer Res 2005; 65(6): 2157-61)

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Purpose: The p53 R72P polymorphism has been suggested to play a role in many cancers, including breast cancer. Our aim was to evaluate association of R72P with breast cancer risk as well as histopathologic features of the breast tumors and survival. Experimental Design: The germ line R72P genotype was defined among 939 Finnish familial and 888 unselected breast cancer patients and 736 healthy population controls. The clinical and biological variables were tested for association by univariate analysis and the effects of several variables on survival by Cox's proportional hazards regression model. Results: The distribution of the genotypes was similar in all groups studied, suggesting no association with breast cancer risk. Unselected breast cancer patients with 72P homozygous genotype presented significantly more often with lobular carcinoma, whereas R72 allele carriers had a significantly higher frequency of ductal carcinomas (P = 0.004). No significant association with other histopathologic variables, like tumor grade, hormone receptor status (estrogen and progesterone receptors), or tumor-node-metastasis stage, was observed. Survival analysis showed that unselected breast cancer patients with 72P homozygous genotype had significantly poorer survival than patients with other genotypes (P = 0.003). This effect on survival was independent of p53 expression in the tumors and multivariate analysis showed that 72P homozygous genotype was overall an independent prognostic factor (risk ratio of death, 2.1; 95% confidence interval, 1.4-3.3; P = 0.001). Conclusions: These results suggest no effect of either R72P allele on breast cancer risk but a significantly reduced survival for 72P homozygous breast cancer patients. The finding of codon 72 genotype as an independent prognostic marker for breast cancer warrants further studies.

Purpose: HuR is an mRNA-binding protein that enhances the stability of certain transcripts and can regulate their translation. Elevated cytoplasmic expression of HuR protein has been linked to carcinogenesis and is associated with reduced survival in breast, ovarian, and gastric adenocarcinomas. Experimental Design: Here, we have explored the relevance of HuR in familial breast cancer. Tumor samples were collected from patients with identified BRCA1 (n = 51) or BRCA2 (n = 47) mutations or familial non-BRCA1/2 cases (n = 525), and analyzed by immunohistochemistry. Results: Among familial non-BRCA1/2 breast cancer patients, cytoplasmic HuR protein expression was present in 39.4% of the cases and was associated with estrogen receptor negativity, progesterone receptor negativity, p53 positivity, high tumor grade, and ductal type of the tumor. In multivariate analysis, cytoplasmic HuR expression was an independent marker of reduced survival in the non-BRCA1/2 group along with tumor size >2 cm, lymph node metastasis, and high histologic grade. In patients with BRCA1 or BRCA2 mutations, cytoplasmic HuR expression was more frequent (62.7% for BRCA1 and 61.7% for BRCA2) than in the non-BRCA1/ 2 group, but in BRCA-mutated subgroups cytoplasmic HuR expression did not associate with survival. Conclusions: Our results show that HuR is an important prognostic factor in familial breast cancer patients and may contribute to carcinogenesis in this disease.Deregulation of gene expression is a hallmark of carcinogenic process. Gene expression is regulated by a series of events that can take place at both transcriptional and posttranscriptional levels. Posttranscriptional regulation of mRNA turnover is an important process in the control of eukaryotic gene expression (1, 2). HuR (or HuA) is a ubiquitously expressed RNA-binding factor related to Drosophila embryonic lethal abnormal vision protein (3). It is a member of the Hu family, and the other three members, HuB/HelN1, HuC, and HuD, are primarily expressed in the neuronal tissues. In unstimulated conditions, HuR is primarily localized to the nucleus but it can shuttle between the nucleus and the cytoplasm. In the nucleus, HuR binds to a Urich motif in the target mRNA and also to certain protein partners, and this complex is then transported to the cytoplasm where HuR can stabilize the transcript and/or regulate its translation (4, 5). Activation of the mitogen-activated protein kinases increase the cytoplasmic content of HuR, which leads to enhanced stability of its target transcripts (6, 7), such as many oncogenic gene products (1, 2).The first link of Hu proteins to carcinogenesis was found in small-cell lung cancer patients, in whom they can act as autoantigens and evoke an immune response against neuronal tissues (8, 9). Elevated HuR expression has been found in highgrade brain tumors (10) and in chemically induced lung tumors in mice (11). The first indication of elevated HuR expression in a human adenocarcinoma was seen in colorectal cancer (12). Lopez de Silanes ...