Prognostic Role of HuR in Hereditary Breast Cancer

Abstract

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 ...

Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients

“…In addition, our results are in accordance to several previously published studies [23][24][25][26][27][28][29][30][31]. In fact, a clinical study conducted on 97 ductal breast carcinoma patients revealed significant associations between elevated total HuR expression (calculated from the combination of staining intensity and extent of positivity in tumor cells) and advanced tumor histological grade and HER2-negative status [23].…”

“…Enhanced HuR expression and cytoplasmic localization have been associated with malignant phenotype and poor patients' prognosis in several human malignancies [18,22]. Interestingly, several studies have further suggested that HuR is implicated in malignant transformation of the breast, however, contradictory data have currently been reported regarding its clinical and prognostic impact in this type of neoplasia [23][24][25][26][27][28][29][30][31]. In view of the above considerations, the present study is aimed to evaluate the immunohistochemical expression of HuR and COX-2 in invasive breast carcinoma in association with multiple clinicopathological characteristics, tumor cells' proliferative capacity and ER, PR and HER2 expression, as well as overall and disease-free patients' survival.…”

Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis

“…The published data has both indicated that HuR overexpression correlates with increased as well as decreased aggressiveness in breast cancer. 23,24,43 These results would lend credence to the idea that HuR may be directing Biosciences) and analysis was performed using Cell Quest software (BD Biosciences).…”

“…[18][19][20][21][22] Increased HuR cytoplasmic expression directly correlates with severity and aggressiveness of many cancers, including those of the breast. [23][24][25] HuR has been demonstrated to be an important prognostic factor in familial breast cancer patients. 23,24 Recently, investigators altered the subcellular distribution of HuR and documented a decrease in mRNA stability, subsequent ER levels and susceptibility to tamoxifen.…”

“…[23][24][25] HuR has been demonstrated to be an important prognostic factor in familial breast cancer patients. 23,24 Recently, investigators altered the subcellular distribution of HuR and documented a decrease in mRNA stability, subsequent ER levels and susceptibility to tamoxifen. 26 In this study we investigated the role of HuR in ER -breast cancer by gain-of-function ER -(MDA-MB-231) cell lines which overexpressed epitope tagged hemagglutinin (HA) HuR.…”