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Activation of Mitogen-Activated Protein Kinase in Estrogen Receptor –Positive Breast Cancer Cells In vitro Induces an In vivo Molecular Phenotype of Estrogen Receptor –Negative Human Breast Tumors

¹ Bioinformatics Program; ² Division of Hematology/Oncology, Department of Internal Medicine; and ³ Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan

Requests for reprints: Dorraya El-Ashry, Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, MSRB III, Room 5220B, Ann Arbor, MI 48109-0640. Phone: 734-764-5585; Fax: 734-764-0101; E-mail: elashryd{at}umich.edu.

Breast cancer presents as either estrogen receptor (ER) positive or negative, with ER+ tumors responding to antiestrogen therapy and having a better prognosis. By themselves, mRNA expression signatures of estrogen regulation in ER+ breast cancer cells do not account for the vast molecular differences observed between ER+ and ER– cancers. In ER– 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 ER+ breast cancer. In ER+/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 ER 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 ER expression and suggest that hyperactivation of MAPK plays a role in the generation of the ER– phenotype in breast cancer. These MAPK+ cell lines are excellent models for investigating the underlying mechanisms behind the ER– phenotype. (Cancer Res 2006; 66(7): 3903-11)

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