Phosphorylation of ERK1/2 mitogen-activated protein kinase is associated with poor response to anti-hormonal therapy and decreased patient survival in clinical breast cancer

Int J Cancer. 2001 Jul 20;95(4):247-54. doi: 10.1002/1097-0215(20010720)95:4<247::aid-ijc1042>;2-s.


It is believed that growth factor phosphorylation cascades interact closely with oestrogen receptor (ER) signaling to regulate breast cancer growth, and that alterations in these pathways may underlie resistance to anti-hormones such as tamoxifen. There is an increasing body of experimental evidence implicating the mitogen-activated protein kinase extracellular signal-regulated-kinases ERK1 and ERK2 (ERK1/2 MAPK) in these events. The present study is the first to address the relationship between ERK1/2 MAPK phosphorylation (p-MAPK) and response to anti-hormonal agents in clinical breast cancer (n = 90). Immunocytochemical analysis using a phosphorylation state-specific ERK1/2 MAPK antibody revealed 72% of breast tumors to have considerable nuclear p-MAPK immunostaining (designated p-MAPK positive), whereas staining was barely detectable or absent in the remaining 28% (designated p-MAPK negative). Comparison with staining in normal breast material obtained from reduction mammoplasty patients (n = 10) demonstrated an increased frequency of higher intensity p-MAPK immunostaining cells within carcinomas (p = 0.002). Significant relationships were revealed between p-MAPK positivity and poorer quality (p = 0.001) and shortened duration (p = 0.006) of anti-hormonal response, as well as with decreased survival time from the initiation of therapy (p = 0.022). These associations were retained in ER positive disease (p = 0.013, p = 0.037 and p = 0.048 respectively), where multivariate analysis demonstrated p-MAPK status to be a significantly independent predictor for response duration (p = 0.034) and patient survival (p = 0.029). Phosphorylated ERK1/2 MAP kinase is thus potentially prognostic for prediction of response to anti-hormonal agents and survival, data providing further evidence that ERK1/2 MAP kinase plays a role in circumvention of anti-hormonal response in breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Case-Control Studies
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • Female
  • Goserelin / administration & dosage
  • Humans
  • Immunohistochemistry
  • MAP Kinase Signaling System
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Multivariate Analysis
  • Phosphorylation
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Statistics, Nonparametric
  • Survival Rate
  • Tamoxifen / administration & dosage


  • Antineoplastic Agents, Hormonal
  • Biomarkers
  • Tamoxifen
  • Goserelin
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases