Transcription profiling by array of breast cancer cell lines and correlations with fibroblast growth factor receptor (FGFR) signalling and repression
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Alan Mackay
PROVIDER: E-MTAB-879 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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2013-01-17 | E-MEXP-3662 | biostudies-arrayexpress
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Project description:A subset of triple negative breast cancers (TNBC) are characterized by genetic alterations in fibroblast growth factor receptors (FGFR) including amplifications, activating mutations or gene fusions. However, despite this genetic evidence of FGFR-dependency, FGFR inhibitors have shown only limited clinical efficacy in TNBC, suggesting the presence of intrinsic or adaptive resistance mechanisms. Using genome-wide CRISPR screens, we found that resistance to FGFR inhibition is mediated by activation of the mTORC1 and YAP pathways. Prolonged FGFR inhibition increased expression of several amino acid transporters resulting in increased cellular level of certain amino acids and activation of the mTORC1 amino acid sensing pathway. Epigenomic analyses revealed that FGFR inhibition reorganized YAP/TEAD associated enhancers leading to the upregulation of YAP target genes including the amino acid transporters upstream of mTORC1. Remarkably, mTORC1 and FGFR inhibitors synergistically blocked the growth of TNBC cells in vitro and in patient-derived xenografts. These findings define a novel epigenetic feedback mechanism involving intracellular amino acid levels leading to targeted therapy resistance in TNBC, and offers a combinatorial drug treatment strategy to improve clinical outcomes for this aggressive breast cancer subtype.
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Project description:A subset of triple negative breast cancers (TNBC) are characterized by genetic alterations in fibroblast growth factor receptors (FGFR) including amplifications, activating mutations or gene fusions. However, despite this genetic evidence of FGFR-dependency, FGFR inhibitors have shown only limited clinical efficacy in TNBC, suggesting the presence of intrinsic or adaptive resistance mechanisms. Using genome-wide CRISPR screens, we found that resistance to FGFR inhibition is mediated by activation of the mTORC1 and YAP pathways. Prolonged FGFR inhibition increased expression of several amino acid transporters resulting in increased cellular level of certain amino acids and activation of the mTORC1 amino acid sensing pathway. Epigenomic analyses revealed that FGFR inhibition reorganized YAP/TEAD associated enhancers leading to the upregulation of YAP target genes including the amino acid transporters upstream of mTORC1. Remarkably, mTORC1 and FGFR inhibitors synergistically blocked the growth of TNBC cells in vitro and in patient-derived xenografts. These findings define a novel epigenetic feedback mechanism involving intracellular amino acid levels leading to targeted therapy resistance in TNBC, and offers a combinatorial drug treatment strategy to improve clinical outcomes for this aggressive breast cancer subtype.
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Project description:We have shown that in PNT1a cells expressing exogenous FGFR4 Arg388 or Gly388 under the control of the EF1 promoter almost all FGFR signaling can be attributed to the transfected receptor, and the two FGFR-4 isoforms are expressed at equivalent levels in the two cell lines. Furthermore, we have shown that serum contains abundant FGFs capable of activating FGFR-4 so these initial experiments were carried out in serum to mimic physiological conditions. In such conditions the Arg388 expressing PNT1a cells display increased invasiveness and motility compared to Gly388 expressing cells. FGFR-4 Arg388 allele shows increased receptor stability and sustained receptor activation following ligand binding when compared to the Gly388 allele. However, the impact of this sustained signaling on cellular signal transduction pathways is unknown. We therefore analyzed the effect of FGFR-4 Arg388 expression on signal transduction in prostatic epithelial cells. We have found that expression of the FGFR-4 Arg388 allele leads to increased activity of the MAPK pathway, increased activity of serum response factor and AP1 and transcription of multiple genes which are correlated with aggressive clinical behavior in prostate cancer. Keywords: two group comparison
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Project description:We have shown that in PNT1a cells expressing exogenous FGFR4 Arg388 or Gly388 under the control of the EF1 promoter almost all FGFR signaling can be attributed to the transfected receptor, and the two FGFR-4 isoforms are expressed at equivalent levels in the two cell lines. Furthermore, we have shown that serum contains abundant FGFs capable of activating FGFR-4 so these initial experiments were carried out in serum to mimic physiological conditions. In such conditions the Arg388 expressing PNT1a cells display increased invasiveness and motility compared to Gly388 expressing cells. FGFR-4 Arg388 allele shows increased receptor stability and sustained receptor activation following ligand binding when compared to the Gly388 allele. However, the impact of this sustained signaling on cellular signal transduction pathways is unknown. We therefore analyzed the effect of FGFR-4 Arg388 expression on signal transduction in prostatic epithelial cells. We have found that expression of the FGFR-4 Arg388 allele leads to increased activity of the MAPK pathway, increased activity of serum response factor and AP1 and transcription of multiple genes which are correlated with aggressive clinical behavior in prostate cancer. Keywords: two group comparison To further understand the underlying molecular mechanisms of increased cell motility and invasiveness in Arg388 expressing cells, microarray studies of biological duplicates were performed on FGFR4 Arg388 and Gly388 expressing PNT1a cells using Agilent 44k whole genome expression microarrays to identify the effector genes that may be responsible for phenotypic differences between the two variants.
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