Human Gene Set: MASRI_RESISTANCE_TO_TAMOXIFEN_AND_AROMATASE_INHIBITORS_DN


Standard name MASRI_RESISTANCE_TO_TAMOXIFEN_AND_AROMATASE_INHIBITORS_DN
Systematic name M1991
Brief description Genes down-regulated in derivatives of MCF-7aro cells (breast cancer) that developed resistance to tamoxifen [PubChem=5376] or inhibitors of aromatase (CYP19A1) [GeneID=1588].
Full description or abstract Acquired resistance to either tamoxifen or aromatase inhibitors (AI) develops after prolonged treatment in a majority of hormone-responsive breast cancers. In an attempt to further elucidate mechanisms of acquired resistance to AIs, MCF-7aro cells resistant to letrozole (T+LET R), anastrozole (T+ANA R), and exemestane (T+EXE R), as well as long-term estrogen deprived (LTEDaro) and tamoxifen-resistant (T+TAM R) lines were generated. This is the first complete panel of endocrine therapy-resistant cell lines, which were generated as multiple independent biological replicates for unbiased genome-wide analysis using affymetrix microarrays. Although similarities are apparent, microarray results clearly show gene signatures unique to AI-resistance were inherently different from LTEDaro and T+TAM R gene expression profiles. Based on hierarchical clustering, unique estrogen-responsive gene signatures vary depending on cell line, with some genes up-regulated in all lines versus other genes up-regulated only in the AI-resistant lines. Characterization of these resistant lines showed that LTEDaro, T+LET R, and T+ANA R cells contained a constitutively active estrogen receptor (ER)alpha that does not require estrogen for activation. This ligand-independent activation of ER was not observed in the parental cells, as well as T+EXE R and T+TAM R cells. Further characterization of these resistant lines was performed using cell cycle analysis, immunofluorescence experiments to visualize ER subcellular localization, as well as cross-resistance studies to determine second-line inhibitor response. Using this well-defined model system, our studies provide important information regarding differences in resistance mechanisms to AIs, TAM, and LTEDaro, which are critical in overcoming resistance when treating hormone-responsive breast cancers.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 18559539   Authors: Masri S,Phung S,Wang X,Wu X,Yuan YC,Wagman L,Chen S
Exact source Table 4S
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Source species Homo sapiens
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Version history 3.0: First introduced


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