Activation of mitogen-activated protein kinase in estrogen receptor α-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor α-negative human breast tumors

Chad J. Creighton, Amy M. Hilger, Shalini Murthy, James M. Rae, Arul M. Chinnaiyan, Dorraya El-Ashry

Research output: Contribution to journalArticle

161 Citations (Scopus)

Abstract

Breast cancer presents as either estrogen receptor α (ERα) positive or negative, with ERα+ tumors responding to antiestrogen therapy and having a better prognosis. By themselves, mRNA expression signatures of estrogen regulation in ERα+ breast cancer cells do not account for the vast molecular differences observed between ERα+ and ERα- cancers. In ERα- tumors, overexpression of epidermal growth factor receptor (EGFR) or c-erbB-2, leading to increased growth factor signaling, is observed such that mitogen-activated protein (MAP) kinase (MAPK) is significantly hyperactivated compared with ERα+ breast cancer. In ERα+/progesterone receptor-positive, estrogen-dependent MCF-7 breast cancer cells, we stably overexpressed EGFR or constitutively active erbB-2, Raf, or MAP/extracellular signal-regulated kinase kinase, resulting in cell lines exhibiting hyperactivation of MAPK, estrogen-independent growth, and the reversible down-regulation of ERα expression. By global mRNA profiling, we found a "MAPK signature" of ∼ 400 genes consistently up-regulated or down-regulated in each of the MAPK+ cell lines. In several independent profile data sets of human breast tumors, the in vitro MAPK signature was able to accurately distinguish ER+ from ER- tumors. In addition, our in vitro mRNA profile data revealed distinct mRNA signatures specific to either erbB-2 or EGFR activation. A subset of breast tumor profiles was found to share extensive similarities with either the erbB-2-specific or the EGFR-specific signatures. Our results confirm that increased MAPK activation causes loss of ERα expression and suggest that hyperactivation of MAPK plays a role in the generation of the ERα- phenotype in breast cancer. These MAPK+ cell lines are excellent models for investigating the underlying mechanisms behind the ERα- phenotype.

Original languageEnglish
Pages (from-to)3903-3911
Number of pages9
JournalCancer Research
Volume66
Issue number7
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

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Mitogen-Activated Protein Kinases
Estrogen Receptors
Breast Neoplasms
Phenotype
Phosphotransferases
Epidermal Growth Factor Receptor
Messenger RNA
Estrogens
In Vitro Techniques
Cell Line
Neoplasms
Estrogen Receptor Modulators
Extracellular Signal-Regulated MAP Kinases
Progesterone Receptors
Mitogens
Intercellular Signaling Peptides and Proteins
Down-Regulation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of mitogen-activated protein kinase in estrogen receptor α-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor α-negative human breast tumors. / Creighton, Chad J.; Hilger, Amy M.; Murthy, Shalini; Rae, James M.; Chinnaiyan, Arul M.; El-Ashry, Dorraya.

In: Cancer Research, Vol. 66, No. 7, 01.04.2006, p. 3903-3911.

Research output: Contribution to journalArticle

Creighton, Chad J. ; Hilger, Amy M. ; Murthy, Shalini ; Rae, James M. ; Chinnaiyan, Arul M. ; El-Ashry, Dorraya. / Activation of mitogen-activated protein kinase in estrogen receptor α-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor α-negative human breast tumors. In: Cancer Research. 2006 ; Vol. 66, No. 7. pp. 3903-3911.
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