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

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165 Scopus citations


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 (US)
Pages (from-to)3903-3911
Number of pages9
JournalCancer Research
Issue number7
StatePublished - Apr 1 2006


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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