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

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 similar to 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 mBNA 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.