Abstract 3271: The RNA binding protein HuR controls angiogenesis in triple negative breast cancer

Abstract

Abstract Due to the poor correlation between steady state mRNA levels and protein products, traditional microarray analysis may miss many genes which are regulated primarily at the level of mRNA stability and translation. Posttranscriptional gene regulation mediated by microRNAs and RNA binding proteins (RBPs) is being recognized as an important form of gene regulation. The elav (embryonic lethal abnormal vision) family of RBPs, are paraneoplastic antigens, over-expressed in a variety of malignancies, including breast cancer. Antibodies against elav family members are believed to be cancer-protective. The elav family binds to the AU-rich elements (AREs) found in the 3’ untranslated regions (UTRs) of many early-response genes, including proto-oncogenes and cell cycle regulators. HuR, the ubiquitously expressed family member, has been described to play a role in cancer progression by stabilizing and translationally up regulating expression of its target mRNAs. Elevated levels of cytoplasmic HuR directly correlate with increased invasiveness of malignancy and poor prognosis for many cancers, including those of the breast. HuR has been described to positively control the expression of multiple genes in the acquired capabilities model, such as VEGF and HIF1α. Hence, it has been suggested that HuR may serve as a tumor maintenance gene which allows for cancers to proliferate. Therefore, it is of interest to discover in vivo HuR targets, as these genes may play vital roles in transformed cells. We have developed methods called RNA immunoprecipitations applied to microarrays, RIP-Chip. We used RIP-Chip to identify distinct subsets of HuR associated mRNAs in MDA-MB-231 and MCF-7 breast cancer cell lines and validated several novel targets. To further investigate the role of HuR in triple negative breast cancer, we over expressed HuR in MDA-MB-231 cells, which results in accelerated growth and alterations in cell cycle kinetics. Surprisingly, when employed in orthotopic mouse models of cancer, HuR over expression significantly inhibited growth of triple negative tumors by 90%. Putative mechanisms appear to be anti-angiogenic, as HuR over expression increases anti-angiogenic factors, but surprisingly, also down regulates pro-angiogenic factors such as VEGF. These results are highly significant because they implicate HuR as a master regulator of angiogenesis in triple negative breast cancer tumor formation and suggest potentially novel treatment methods for this aggressive form of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3271.