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

Abstract

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 that 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)

Gene expression abnormalities in histologically normal breast epithelium of breast cancer patients

“…The largest number participates directly in the MAPK pathway, and others may affect MAPK signaling more peripherally. Consid- 41,42 In contrast, we found decreased expression of MAPK components, which could be related to using tissue from ER-positive tumors, or may reflect an initial step in the pathway's perturbation. A final consideration is how can these data be utilized.…”

Breast cancer genome-wide association studies: there is strength in numbers

“…MAP3K1 forms part of the MAPK cell signaling pathway implicated in cellular response to mitogens. The MAPK pathway is strongly linked to HER2 receptor activity and activating mutations in the MAPK pathway have been associated with HER2 þ breast tumors (Bild et al, 2006;Creighton et al, 2006). MAP3K1 was identified by Easton et al (2007) to have a per-allele odds ratio effect of 1.13 (95% confidence interval: 1.09-1.18).…”

Estrogen receptor-positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss

“…Recent findings revealing distinctive molecular profiles for ERÀ tumors containing ErbB1 versus ErbB2 (Creighton et al, 2006) may shed light on these differences. Cystic papillary tumors in NRL-TGFa mice resemble those of other TGFa transgenic mice (Humphreys and Hennighausen, 2000;Rose-Hellekant and Sandgren, 2000;Arendt et al, 2006).…”