title: Low ERK phosphorylation in cancer-associated fibroblasts is associated with tamoxifen resistance in pre-menopausal breast cancer.
abstract: OBJECTIVE
  The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial.
  
  
  METHODS
  Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMAα) in cancer-associated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated.
  
  
  RESULTS
  By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ERα-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis). In both clinical materials we further show a significant association between pERK and SMAα, a characteristic marker for activated fibroblasts. SMAα expression however was not linked to treatment-predictive information but instead had prognostic qualities.
  
  
  CONCLUSIONS
  The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer.
authors.affiliation: Breakthrough Breast Cancer Research Unit, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester Academic Health Science Centre, Paterson Institute for Cancer Research, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Susann
authors.initials: S
authors.lastname: Busch
authors.forename: Lisa
authors.initials: L
authors.lastname: Rydén
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
mesh_terms: D000199:Actins / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015331:Cohort Studies; D047628:Estrogen Receptor alpha / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D010766:Phosphorylation; D017697:Premenopause; D013629:Tamoxifen / Q000627:therapeutic use*; D046888:Tissue Array Analysis
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D048049:Extracellular Signal-Regulated MAP Kinases