Highlights d Kinase inhibitors (KIs) and biguanides synergistically target cancer cells d mTORC1/4E-BP axis regulates aspartate, asparagine, and serine biosynthetic enzymes d 4E-BPs and HIF-1a determine responses to KI/biguanide combinations d Cancer cell metabolic plasticity limits efficacy of the KI/ biguanide combinations

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-celllike 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.

Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer‐associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5′UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome association remains unaltered are enriched in codons requiring U34‐modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34‐modifying enzymes and thereby controls levels of U34‐modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα‐dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone‐dependent cancers.

Dysregulated mRNA translation and aberrant energy metabolism are frequent in cancer. Considering that mRNA translation is an energy demanding process, cancer cells must produce sufficient ATP to meet energy demand of hyperactive translational machinery. In recent years, the mammalian/mechanistic target of rapamycin (mTOR) emerged as a central regulatory node which coordinates energy consumption by the translation apparatus and ATP production in mitochondria. Aberrant mTOR signaling underpins the vast majority of cancers whereby increased mTOR activity is thought to be a major determinant of both malignant translatomes and metabolomes. Nonetheless, the role of mTOR and other related signaling nodes (e.g. AMPK) in orchestrating protein synthesis and cancer energetics is only recently being unraveled. In this review, we discuss recent findings that provide insights into the molecular underpinnings of coordination of translational and metabolic programs of cancer cells, and potential strategies to translate these findings into clinical treatments.

Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.