IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG

• Published in: Oncogene Vol. 35; no. 9; pp. 1111 - 1121
• Main Authors: Samanta, S, Sun, H, Goel, H L, Pursell, B, Chang, C, Khan, A, Greiner, D L, Cao, S, Lim, E, Shultz, L D, Mercurio, A M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.03.2016; Nature Publishing Group
• Subjects: 13; 38; 45; 5' Untranslated Regions; 631/67/1347; Apoptosis; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Breast cancer; Care and treatment; Cell Biology; Cell self-renewal; Complications and side effects; Gene expression; Gene Expression Regulation, Neoplastic; Human Genetics; Humans; Influence; Insulin; Internal Medicine; Medicine; Medicine & Public Health; Metastasis; Neoplastic Stem Cells; Oncology; original-article; Phenotypes; Prognosis; Protein binding; Ribonucleic acid; Risk factors; RNA; RNA, Messenger - biosynthesis; RNA-Binding Proteins - biosynthesis; RNA-Binding Proteins - genetics; Snail Family Transcription Factors; Snail protein; SOXB1 Transcription Factors - genetics; Stem cell factor; Stem cell research; Stem cells; Transcription; Transcription Factors - biosynthesis; Transcription Factors - genetics; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.164

IMP3 (insulin-like growth factor-2 mRNA binding protein 3) is an oncofetal protein whose expression is prognostic for poor outcome in several cancers. Although IMP3 is expressed preferentially in triple-negative breast cancer (TNBC), its function is poorly understood. We observed that IMP3 expression is significantly higher in tumor initiating than in non-tumor initiating breast cancer cells and we demonstrate that IMP3 contributes to self-renewal and tumor initiation, properties associated with cancer stem cells (CSCs). The mechanism by which IMP3 contributes to this phenotype involves its ability to induce the stem cell factor SOX2. IMP3 does not interact with SOX2 mRNA significantly or regulate SOX2 expression directly. We discovered that IMP3 binds avidly to SNAI2 ( SLUG ) mRNA and regulates its expression by binding to the 5' UTR. This finding is significant because SLUG has been implicated in breast CSCs and TNBC. Moreover, we show that SOX2 is a transcriptional target of SLUG. These data establish a novel mechanism of breast tumor initiation involving IMP3 and they provide a rationale for its association with aggressive disease and poor outcome.