Translational control of breast cancer plasticity
It is shown that unique mRNA isoforms that govern stem cell-like phenotypes escape translational repression to drive tumor progression and chemoresistance and provide a molecular basis for therapeutic strategies aimed at overcoming drug resistance and abrogating metastasis.
Abstract
<jats:title>Abstract</jats:title> <jats:p> 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 <jats:italic>NANOG</jats:italic> , <jats:italic>SNAIL</jats:italic> and <jats:italic>NODAL</jats:italic> 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 <jats:italic>NANOG</jats:italic> , <jats:italic>SNAIL</jats:italic> and <jats:italic>NODAL</jats:italic> 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. </jats:p>