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
Tumor cells utilize glucose as a primary energy source and require ongoing lipid biosynthesis for growth. Expression of DecR1, an auxiliary enzyme in the fatty acid -oxidation pathway, is significantly diminished in numerous spontaneous mammary tumor models and in primary human breast cancer. Moreover, ectopic expression of DecR1 in ErbB2/Neu-induced mammary tumor cells is sufficient to reduce levels of ErbB2/Neu expression and impair mammary tumor outgrowth. This correlates with a decreased proliferative index and reduced rates of de novo fatty acid synthesis in DecR1-expressing breast cancer cells. Although DecR1 expression does not affect glucose uptake in ErbB2/Neu-transformed cells, sustained expression of DecR1 protects mammary tumor cells from apoptotic cell death following glucose withdrawal. Moreover, expression of catalytically impaired DecR1 mutants in Neu-transformed breast cancer cells restored Neu expression levels and increased mammary tumorigenesis in vivo. These results argue that DecR1 is sufficient to limit breast cancer cell proliferation through its ability to limit the extent of oncogene expression and reduce steady-state levels of de novo fatty acid synthesis. Furthermore, DecR1-mediated suppression of tumorigenesis can be uncoupled from its effects on Neu expression. Thus, while downregulation of Neu expression may contribute to DecR1-mediated tumor suppression in certain cell types, this is not an obligate event in all Neu-transformed breast cancer cells.
Eukaryotic initiation factor 4E (eIF4E) is the subunit of eIF4F that binds to the cap structure at the 5 end of messenger RNA and is a critical component for the regulation of translation initiation. Using 7-methyl-GTPSepharose affinity chromatography, two distinct capbinding proteins that migrate on SDS-polyacrylamide gel electrophoresis at approximately 35 kDa were purified from Drosophila adults. Peptide microsequence analysis indicated that these two proteins differ at their amino termini. Analysis of a set of cDNA clones encoding eIF4E led to the conclusion that the two different protein isoforms, which we term eIF4EI and eIF4EII, result from three alternatively spliced transcripts from a single eIF4E gene, which maps to region 67A8-B2 on polytene chromosomes. The three eIF4E transcripts also vary greatly in the lengths of their 5-UTRs, suggesting the possibility of complex translational control of expression of the two eIF4E isoforms.
Rab Coupling Protein (FIP1C), an effector of the Rab11 GTPases, including Rab25, is amplified and overexpressed in 10-25% of primary breast cancers and correlates with poor clinical outcome. Rab25 is also frequently silenced in triple negative breast cancer, suggesting its ability to function as either an oncogene or a tumor suppressor, depending on the breast cancer subtype. However, the patho-biological role of FIP family members, such as FIP1C, in a tumor-specific setting remains elusive. In this study, we used ErbB2 mouse models of human breast cancer to investigate FIP1C function in tumorigenesis. Doxycycline-induced expression of FIP1C in the MMTV-ErbB2 mouse model resulted in delayed mammary tumor progression. Conversely, targeted deletion of FIP1C in the mammary epithelium of an ErbB2 model co-expressing Cre recombinase led to accelerated tumor onset. Genetic and biochemical characterization of these FIP1C-proficient and deficient tumor models revealed that FIP1C regulated E-cadherin (CDH1) trafficking and ZONAB (YBX3) function in Cdk4-mediated cell cycle progression. Furthermore, we demonstrate that FIP1C promoted lysosomal degradation of ErbB2. Consistent with our findings in the mouse, the expression of FIP1C was inversely correlated with ErbB2 levels in breast cancer patients. Taken together, our findings indicate that FIP1C acts as a tumor suppressor in the context ErbB2-positive breast cancer, and may be therapeutically exploited as an alternative strategy for targeting aberrant ErbB2 expression.
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.
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