PloS one · 2010
ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways.
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Lin Sheng-Li, Yan Li-Ying, Zhang Xin-Tian, Yuan Ju, Li Mo, Qiao Jie, Wang Zhao-Yi, Sun Qing-Yuan
Аннотация
BACKGROUND: Recently, a novel variant of ER-alpha, ER-alpha36 was identified and cloned. ER-alpha36 lacks intrinsic transcription activity and mainly mediates nongenomic estrogen signaling. Here, we studied the role of nongenomic estrogen signaling pathways mediated by ER-alpha36 in tamoxifen resistance and agonist action.
METHODOLOGY: The cellular localization of ER-alpha36 was examined by immunofluorescence in MCF-7 cells and Hec1A cells. MCF-7 breast cancer cells, MCF-7 cells expressing recombinant ER-alpha36 (MCF-7/ER36), Hec1A endometrial cancer cells and Hec1A cells with siRNA knockdown of ER-alpha36 (Hec1A/RNAiER36) were treated with 17beta-estradial (E2) and tamoxifen (TAM) in the absence and presence of kinase inhibitor U0126 and LY294002. We examined phosphorylation of signaling molecules and the expression of c-Myc by immunoblotting, and tumor cell growth by MTT assay.
CONCLUSIONS: ER variant ER-alpha36 enhances TAM agonist activity through activation of the membrane-initiated signaling pathways in endometrial cancer, and that ER-alpha36 is involved in de novo and acquired TAM resistance in breast cancer.
METHODOLOGY: The cellular localization of ER-alpha36 was examined by immunofluorescence in MCF-7 cells and Hec1A cells. MCF-7 breast cancer cells, MCF-7 cells expressing recombinant ER-alpha36 (MCF-7/ER36), Hec1A endometrial cancer cells and Hec1A cells with siRNA knockdown of ER-alpha36 (Hec1A/RNAiER36) were treated with 17beta-estradial (E2) and tamoxifen (TAM) in the absence and presence of kinase inhibitor U0126 and LY294002. We examined phosphorylation of signaling molecules and the expression of c-Myc by immunoblotting, and tumor cell growth by MTT assay.
CONCLUSIONS: ER variant ER-alpha36 enhances TAM agonist activity through activation of the membrane-initiated signaling pathways in endometrial cancer, and that ER-alpha36 is involved in de novo and acquired TAM resistance in breast cancer.
Предметные рубрики MeSH
Alternative SplicingAntineoplastic Agents, HormonalBlotting, WesternButadienesCell Line, TumorCell MembraneCell ProliferationChromonesDose-Response Relationship, DrugEndometrial NeoplasmsEnzyme ActivationEstrogen Receptor alphaEstrogensExtracellular Signal-Regulated MAP KinasesFemaleHumansMorpholinesNitrilesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein IsoformsProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-mycRNA InterferenceSignal TransductionTamoxifen