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

Open Access
Publisher Website
Google Scholar
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. (Cancer Res 2006; 66(7): 3903-11)