Dataset Information

ERR? mediates metabolic adaptations driving lapatinib resistance in breast cancer.

ABSTRACT: Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERR?, a master regulator of cellular metabolism, and that the expression of ERR? is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERR? in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERR? inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERR?-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERR? inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.

SUBMITTER: Deblois G

PROVIDER: S-EPMC4945959 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer.

Deblois Geneviève G Smith Harvey W HW Tam Ingrid S IS Gravel Simon-Pierre SP Caron Maxime M Savage Paul P Labbé David P DP Bégin Louis R LR Tremblay Michel L ML Park Morag M Bourque Guillaume G St-Pierre Julie J Muller William J WJ Giguère Vincent V

Nature communications 20160712

Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitoch ...[more]

PMID: 27402251

Similar Datasets

Project description:The Kruppel-like transcription factors (KLFs) 4 and 5 (KLF4/5) are coexpressed in mouse embryonic stem cells, where they function redundantly to maintain pluripotency. In mammary carcinoma, KLF4/5 can each impact the malignant phenotype, but potential linkages to drug resistance remain unclear. In primary human breast cancers, we observed a positive correlation between KLF4/5 transcript abundance, particularly in the human epidermal growth factor receptor 2 (HER2)-enriched subtype. Furthermore, KLF4/5 protein was rapidly upregulated in human breast cancer cells following treatment with the HER2/epidermal growth factor receptor inhibitor, lapatinib. In addition, we observed a positive correlation between these factors in the primary tumors of genetically engineered mouse models (GEMMs). In particular, the levels of both factors were enriched in the basal-like tumors of the C3(1) TAg (SV40 large T antigen transgenic mice under control of the C3(1)/prostatein promoter) GEMM. Using tumor cells derived from this model as well as human breast cancer cells, suppression of KLF4 and/or KLF5 sensitized HER2-overexpressing cells to lapatinib. Indicating cooperativity, greater effects were observed when both genes were depleted. KLF4/5-deficient cells had reduced basal mRNA and protein levels of the anti-apoptotic factors myeloid cell leukemia 1 (MCL1) and B-cell lymphoma-extra large (BCL-XL). Moreover, MCL1 was upregulated by lapatinib in a KLF4/5-dependent manner, and enforced expression of MCL1 in KLF4/5-deficient cells restored drug resistance. In addition, combined suppression of KLF4/5 in cultured tumor cells additively inhibited anchorage-independent growth, resistance to anoikis and tumor formation in immunocompromised mice. Consistent with their cooperative role in drug resistance and other malignant properties, KLF4/5 levels selectively stratified human HER2-enriched breast cancer by distant metastasis-free survival. These results identify KLF4 and KLF5 as cooperating protumorigenic factors and critical participants in resistance to lapatinib, furthering the rationale for combining anti-MCL1/BCL-XL inhibitors with conventional HER2-targeted therapies.

Dataset Information

ERR? mediates metabolic adaptations driving lapatinib resistance in breast cancer.

Publications

ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets