title: 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.
abstract: 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.
authors.affiliation: Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom. gee@cardiff.ac.uk
authors.forename: J M
authors.initials: JM
authors.lastname: Gee
authors.forename: J F
authors.initials: JF
authors.lastname: Robertson
authors.forename: I O
authors.initials: IO
authors.lastname: Ellis
authors.forename: R I
authors.initials: RI
authors.lastname: Nicholson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D017273:Goserelin / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015999:Multivariate Analysis; D010766:Phosphorylation; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D018709:Statistics, Nonparametric; D015996:Survival Rate; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D013629:Tamoxifen; D017273:Goserelin; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases