Abstract 5020: Role of LIN28 in aggressive breast cancers lacking REST

Abstract

Abstract Our lab has discovered a highly aggressive subset of breast cancers characterized by a lack of function of the tumor suppressor RE1 Silencing Transcription Factor (REST). REST is a transcriptional repressor controlling over 2000 neuronal genes, and has been identified as a tumor suppressor in lung and colon cancers. Our lab has discovered that REST function is lost in 20% of breast tumors and that its loss is associated with a significantly decreased disease-free survival and poor prognosis (Wagoner et al. poster, this meeting, CB4). In addressing the mechanisms underlying the aggressiveness of these RESTless tumors, we found that expression of the tumor promoter LIN28 is upregulated. We describe the direct regulation of LIN28 by REST in a range of mammary cell lines and show a correlation between REST loss and LIN28 overexpression in breast tumors. LIN28 inhibits maturation of the tumor suppressor microRNA let-7, which in turn suppresses expression of the oncogenes Myc and Ras. LIN28 overexpression has been found to promote metastasis in a mouse xenograft model of breast cancer. To examine the effects of REST loss and LIN28 expression on cellular transformation and motility, we have knocked down REST and LIN28 in a variety of breast cell lines (including T47D, MCF7, MDA-MB-231, 3T3 and NMuMG cells). Here, we describe the results of our colony formation, soft agar growth and motility assays. We recapitulate in vitro aspects of tumor aggression seen in the patient population, and we find that these processes are promoted by REST loss in a LIN28-dependent manner. We also describe xenograft models looking at the growth and metastasis of tumors that express or lack REST and LIN28. We conclude that REST loss promotes tumor aggressiveness at least in part via upregulation of its target gene LIN28. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 5020.