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Posttranscriptional Regulation of the Breast Cancer Susceptibility Gene BRCA1 by the RNA Binding Protein HuR

¹ School of Molecular and Microbial Sciences, The University of Queensland and ² The Princess Alexandra Hospital, Woolloongabba, Queensland, Australia; ³ Laboratory for Cancer Medicine, the UWA Centre for Medical Research, Western Australian Institute for Medical Research and School of Medicine and Pharmacology, The University of Western Australia and ⁴ Department of Medical Oncology, Royal Perth Hospital, Perth, Australia; and ⁵ Department of Biochemistry and Molecular Biology, The University of Melbourne, Victoria, Australia

Requests for reprints: Melissa Brown, School of Molecular and Microbial Sciences, The University of Queensland, St Lucia, Queensland 4072, Australia. Phone: 61-7-3365-4628; Fax: 61-7-3365-4699; E-mail: melissa.brown{at}uq.edu.au.

Key Words: BRCA1 • HuR • posttranscriptional regulation • 3'UTR • breast cancer

BRCA1 is a breast cancer susceptibility gene that is down-regulated in a significant proportion of sporadic breast cancers. BRCA1 is posttranscriptionally regulated by RNA-binding proteins, the identities of which are unknown. HuR is an RNA binding protein implicated in posttranscriptional regulation of many genes and is overexpressed in sporadic breast cancer. To investigate the possibility that these two molecules are functionally linked in breast cancer, we performed bioinformatic analysis of the BRCA1 3' untranslated region (UTR), RNA-protein assays with the HuR protein and the BRCA1 3'UTR, and immunohistochemical analysis of a cohort of breast tumors using antibodies against BRCA1 and HuR. Here, we describe the identification of two predicted HuR-binding sites in the BRCA1 3'UTR, one of which binds specifically to HuR. We also show that this interaction is disrupted by single nucleotide substitutions in the BRCA1 3'UTR and that endogenous HuR protein associates with BRCA1 transcripts in T47D and MCF7 breast cancer cells. Expression of ectopic HuR results in a significant decrease in BRCA1 protein expression and also BRCA1 3'UTR activity. Immunohistochemical analysis revealed that although BRCA1 and HuR expression were associated with some clinicopathologic features of the tumors, there was no statistically significant correlation between BRCA1 and HuR protein expression. These results identify the first posttranscriptional protein regulator of BRCA1 and have implications for understanding BRCA1 regulation in human breast cancer. [Cancer Res 2008;68(22):9469–78]