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Submitted on February 5, 2004
Accepted on March 22, 2004
Downregulation in Breast Cancer Cells: The Role of NFkB
Lombardi Cancer Center, Georgetown University; University of Michigan Comprehensive Cancer Center
* To whom correspondence should be addressed. E-mail: elashryd{at}umich.edu.
Estrogen receptor 
(ER) 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 previously shown that ER(+) MCF-7 cells with elevated growth factor signaling lose expression of ER without any ligand-independent transcriptional activation, and this is a reversible effect attributable to ERK1/2 hyperactivation. Here, we show that down-regulation of ER is not mediated by a specific ERK-1 vs. ERK-2 substrate. Despite upregulated AP-1 activity in response to ERK1/2 activation, and in ER(-) and hormone-independent breast cancers, we find that increased AP-1 activity is not responsible for ER 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 ER in our models. On the other hand, inhibition of NFkB (which is linked to chemoresistance in cancer in general, and has elevated activity in hormone independent and ER- breast cancer) significantly enhances ER activity, suggesting that indirect elevation in NFkB activity (due to hyperactive ERK1/2) is at least partially responsible for ER down-regulation in these cell line models.
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