Human Gene Set: CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_4


Standard name CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_4
Systematic name M6386
Brief description The 'group 4 set' of genes associated with acquired endocrine therapy resistance in breast tumors expressing ESR1 but not ERBB2 [GeneID=2099;2064].
Full description or abstract The effectiveness of therapies targeting specific pathways in breast cancer, such as the estrogen receptor or HER2, is limited because many tumors manifest resistance, either de novo or acquired, during the course of treatment. To investigate molecular mechanisms of resistance, we used two xenograft models of estrogen receptor-positive (ER+) breast cancer, one with and one without HER2 overexpression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for gene expression and compared with tumors in the E2 control group. One class of genes underexpressed in endocrine-resistant tumors (relative to E2-treated tumors) were estrogen inducible in vitro and associated with ER+ human breast cancers (luminal subtype). Another class of genes overexpressed in tumors with acquired resistance in both models represented transcriptional targets of HER2 signaling and was associated with ER-/HER2+ human cancers (ERBB2+ subtype). A third class of genes overexpressed in MCF7/HER2-18 tumors exhibiting de novo resistance to tamoxifen was associated with ER+ human cancers but not with estrogen-regulated genes. Thus, in response to various endocrine therapy regimens, these xenograft breast tumors shut down classic estrogen signaling and activate alternative pathways such as HER2 that contribute to treatment resistance. Over time, the molecular phenotype of breast cancer can change.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 18794137   Authors: Creighton CJ,Massarweh S,Huang S,Tsimelzon A,Hilsenbeck SG,Osborne CK,Shou J,Malorni L,Schiff R
Exact source Suppl. Data File 1: WT_Group4
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Source species Homo sapiens
Contributed by Jessica Robertson (MSigDB Team)
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identifier namespace		 AFFY_HG_U133
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Version history 3.0: First introduced

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