Abstract 5012: REST is lost in aggressive breast cancer through an aberrant splicing loop

Abstract

Abstract Transcriptional profiling of breast tumors has lead to new diagnostic tools allowing better prediction of disease recurrence and response to treatment, but does little to elucidate mechanisms responsible for the differential disease course. Using transcriptional profiling we show for the first time that a subset of breast tumors lack the tumor suppressor RE1 silencing transcription factor (REST), a master repressor of neuronal genes. Loss of REST is sufficient to induce anchorage independent cell growth in human mammary epithelial cells, and we find that these REST-less tumors show a highly aggressive disease course independent of tumors grade, size or subtype. Importantly, these aggressive tumors overexpress the tumor promoter and REST target gene Lin28, which may be responsible for the aggressive phenotype of these tumors (Gunsalus et al. poster, AACR 2010 CB4). We find that loss of REST function occurs in breast cancer via alternative splicing of the tumor suppressor to a truncated form normally observed in the brain following seizures. Here, we show that REST regulates its own aberrant splicing in an intriguing positive-feedback loop that results in a loss of REST function. These results identify a previously unknown subset of aggressive cancers, the transcription factor responsible for unique molecular profile, and the novel positive feedback pathway responsible for the aberrant splicing. 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 5012.