TY - JOUR
T1 - 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
AU - Creighton, Chad J.
AU - Hilger, Amy M.
AU - Murthy, Shalini
AU - Rae, James M.
AU - Chinnaiyan, Arul M.
AU - El-Ashry, Dorraya
PY - 2006/4/1
Y1 - 2006/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33645730357&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645730357&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-4363
DO - 10.1158/0008-5472.CAN-05-4363
M3 - Article
C2 - 16585219
AN - SCOPUS:33645730357
SN - 0008-5472
VL - 66
SP - 3903
EP - 3911
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -