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.