A cytoplasmic substrate of mitogen-activated protein kinase is responsible for estrogen receptor-α down-regulation in breast cancer cells

The role of nuclear factor-κB

Jamie N. Holloway, Shalini Murthy, Dorraya El-Ashry

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Estrogen receptor α (ERα) 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 ERα(+) MCF-7 cells with elevated growth factor signaling lose expression of ERα without any ligand-independent transcriptional activation, and this is a reversible effect attributable to ERK1/2 hyperactivation. Here, we show that down-regulation of ERα 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 ERα(-) and hormone-independent breast cancers, we find that increased activator protein-1 activity is not responsible for ERα 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 ERα in our models. On the other hand, inhibition of nuclear factor-κB (which is linked to chemoresistance in cancer in general and has elevated activity in hormone-independent and ERα - breast cancer) significantly enhances ERα activity, suggesting that indirect elevation in nuclear factor-κB activity (due to hyperactive ERK1/2) is at least partially responsible for ERα down-regulation in these cell line models.

Original languageEnglish
Pages (from-to)1396-1410
Number of pages15
JournalMolecular Endocrinology
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2004
Externally publishedYes

Fingerprint

Mitogen-Activated Protein Kinases
Estrogen Receptors
Down-Regulation
Breast Neoplasms
Transcription Factor AP-1
Intercellular Signaling Peptides and Proteins
Hormones
Growth Factor Receptors
MCF-7 Cells
Transcriptional Activation
Ligands
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

A cytoplasmic substrate of mitogen-activated protein kinase is responsible for estrogen receptor-α down-regulation in breast cancer cells : The role of nuclear factor-κB. / Holloway, Jamie N.; Murthy, Shalini; El-Ashry, Dorraya.

In: Molecular Endocrinology, Vol. 18, No. 6, 01.06.2004, p. 1396-1410.

Research output: Contribution to journalArticle

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