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[Cancer Research 66, 3903-3911, April 1, 2006]
© 2006 American Association for Cancer Research

Endocrinology

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

Chad J. Creighton1, Amy M. Hilger2, Shalini Murthy2, James M. Rae2, Arul M. Chinnaiyan3 and Dorraya El-Ashry2

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




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