A cytoplasmic substrate of mitogen-activated protein kinase is responsible for estrogen receptor-alpha down-regulation in breast cancer cells: the role of nuclear factor-kappaB.
Estrogen receptor alpha (ERalpha) negative breast tumors often present with enhanced expression and/or activation of growth factor receptors, resulting in increased growth factor signaling and hyperactivation of MAPK (ERK1 and ERK2). We have pre-viously shown that ERalpha(+) MCF-7 cells with elevated growth factor signaling lose expression of ERalpha without any ligand-independent transcriptional activation, and this is a reversible effect attributable to ERK1/2 hyperactivation. Here, we show that down-regulation of ERalpha is not mediated by a specific ERK-1 vs. ERK-2 substrate. Despite up-regulated activator protein-1 activity in response to ERK1/2 activation, and in ERalpha(-) and hormone-independent breast cancers, we find that increased activator protein-1 activity is not responsible for ERalpha down-regulation. Interestingly, our findings implicate a cytoplasmic substrate of ERK1/2. However, RSK1, the best-characterized cytoplasmic ERK1/2 substrate, does not down-regulate ERalpha in our models. On the other hand, inhibition of nuclear factor-kappaB (which is linked to chemoresistance in cancer in general and has elevated activity in hormone-independent and ERalpha- breast cancer) significantly enhances ERalpha activity, suggesting that indirect elevation in nuclear factor-kappaB activity (due to hyperactive ERK1/2) is at least partially responsible for ERalpha down-regulation in these cell line models.
Holloway
Jamie N
JN
Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA.
Murthy
Shalini
S
El-Ashry
Dorraya
D
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005822:Genetic Vectors; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D047628:Estrogen Receptor alpha; D006133:Growth Substances; D008024:Ligands; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3