Journal Article

Translational control of breast cancer plasticity

Lee, Laura, Brumwell, Andrea, Jewer, Michael, Liu, Jiahui, Leibovitch, Matthew, Zhang, Guihua, Guan, Bo-Jhih, Vincent, Krista M., Puri, Aakshi, Siegers, Gabrielle M., Hatzoglou, Maria, Dieters-Castator, Dylan, Koromilas, Antonis, Schueler, Julia, Topisirovic, Ivan, Findlay, Scott D., Xu, Zhihua, Coatham, Mackenzie, Patsis, Christos, Postovit, Lynne-Marie, Quail, Daniela F., Uniacke, James, Tandoc, Kristofferson, Dutta, Indrani

2020

Overview

Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast cancer cells NANOG , SNAIL and NODAL transcripts manifest multiple isoforms characterized by different 5’ Untranslated Regions (5’UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. The accumulation of the corresponding proteins induces plasticity and “fate-switching” toward stem cell-like phenotypes. Mechanistically, we observe that mTOR inhibitors and chemotherapeutics induce translational activation of a subset of NANOG , SNAIL and NODAL mRNA isoforms akin to hypoxia, engendering stem-cell-like phenotypes. These effects are overcome with drugs that antagonize translational reprogramming caused by eIF2α phosphorylation (e.g. ISRIB), suggesting that the Integrated Stress Response drives breast cancer plasticity. Collectively, our findings reveal a mechanism of induction of plasticity of breast cancer cells and provide a molecular basis for therapeutic strategies aimed at overcoming drug resistance and abrogating metastasis. Protein synthesis suppression protects breast cancer cells from clinically relevant stresses like hypoxia. Here, the authors show that unique mRNA isoforms that govern stem cell-like phenotypes escape translational repression to drive tumor progression and chemoresistance.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/100 / 38 / 38/77 / 5' Untranslated regions / 5' Untranslated Regions - genetics / 631/67/1347 / 631/80/86/2366 / 64 / 64/60 / 82/80 / 96 / 96/95 / Antineoplastic Agents - pharmacology / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cell Hypoxia / Cell Line, Tumor / Chemoresistance / Chemotherapy / Disease progression / Drug resistance / Eukaryotic Initiation Factor-2 - genetics / Eukaryotic Initiation Factor-2 - metabolism / Female / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - genetics / Humanities and Social Sciences / Humans / Hypoxia / Isoforms / MCF-7 Cells / Metastases / multidisciplinary / Nanog Homeobox Protein - genetics / Nodal Protein - genetics / Phenotypes / Phosphorylation / Phosphorylation - drug effects / Plastic properties / Plasticity / Protein biosynthesis / Protein Biosynthesis - genetics / Protein synthesis / Proteins / RNA Isoforms - genetics / Science / Science (multidisciplinary) / Snail Family Transcription Factors - genetics / Stem cells / TOR protein / Translation