17beta-estradiol and tamoxifen stimulate rapid and transient ERK activationin MCF-7 cells via distinct signaling mechanisms.
Traditionally, estrogen signaling was thought to be mediated strictly through genomic pathways. Recently, however, it has been demonstrated that estrogen stimulation of cells leads to rapid nongenomic effects including ERK activation. While the precise mechanism of this action is still under investigation, it is known that activation of the epidermal growth factor receptor, the Src tyrosine kinase, and metalloproteinases are involved in this process. More recently, tamoxifen, an anti-hormonal agent used to treat breast cancer, has been shown to also activate ERK. The pathways by which it does so, however, are not known. Using the MCF-7 human breast carcinoma cell line as a model system, we show that ERK is rapidly and transiently activated in cells challenged with epidermal growth factor (EGF), 17beta-estradiol (E2) or tamoxifen. The ERK activation response to E2 and tamoxifen was kinetically similar, although the response to tamoxifen was delayed relative to that of E2 stimulation. The effect of the EGFR inhibitor AG1517 revealed that E2 and tamoxifen were both equally dependent on EGFR for activation of ERK. In contrast, inhibition of Src or metalloproteinases caused distinct effects on ERK activation by E2 and tamoxifen. Thus, while both E2 and tamoxifen induced activation of ERK, the differences in the effects of inhibitors of Src or metalloproteinases on ERK activation indicated that E2 and tamoxifen do so via distinct molecular mechanisms.
Visram
Hasina
H
Department of Pathology and Molecular Medicine, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Greer
Peter A
PA
D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology*
D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D004958:Estradiol; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases