Activation of Mitogen-Activated Protein Kinase in Estrogen Receptor α–Positive Breast Cancer CellsIn vitroInduces anIn vivoMolecular 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
2006 Cancer Research  
Breast cancer presents as either estrogen receptor A (ERA) positive or negative, with ERA+ tumors responding to antiestrogen therapy and having a better prognosis. By themselves, mRNA expression signatures of estrogen regulation in ERA+ breast cancer cells do not account for the vast molecular differences observed between ERA+ and ERAÀ cancers. In ERAÀ tumors, overexpression of epidermal growth factor receptor (EGFR) or c-erbB-2, leading to increased growth factor signaling, is observed such
more » ... t mitogen-activated protein (MAP) kinase (MAPK) is significantly hyperactivated compared with ERA+ breast cancer. In ERA+/progesterone receptor-positive, estrogen-dependent MCF-7 breast cancer cells, we stably overexpressed EGFR or constitutively active erbB-2, Raf, or MAP/extracellular signalregulated kinase kinase, resulting in cell lines exhibiting hyperactivation of MAPK, estrogen-independent growth, and the reversible down-regulation of ERA expression. By global mRNA profiling, we found a "MAPK signature" of f400 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 ERÀ 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 EGFRspecific signatures. Our results confirm that increased MAPK activation causes loss of ERA expression and suggest that hyperactivation of MAPK plays a role in the generation of the ERAÀ phenotype in breast cancer. These MAPK+ cell lines are excellent models for investigating the underlying mechanisms behind the ERAÀ phenotype. (Cancer Res 2006; 66(7): 3903-11) Requests for reprints:
doi:10.1158/0008-5472.can-05-4363 pmid:16585219 fatcat:5k5lmritbfazbghfhut33ad5ey