title: Histological evaluation of AMPK signalling in primary breast cancer.
abstract: BACKGROUND
  AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge that responds to energy stress by suppressing cell growth and biosynthetic processes, thus ensuring that energy-consuming processes proceed only if there are sufficient metabolic resources. Malfunction of the AMPK pathway may allow cancer cells to undergo uncontrolled proliferation irrespective of their molecular energy levels. The aim of this study was to examine the state of AMPK phosphorylation histologically in primary breast cancer in relation to clinical and pathological parameters.
  
  
  METHODS
  Immunohistochemistry was performed using antibodies to phospho-AMPK (pAMPK), phospho-Acetyl Co-A Carboxylase (pACC) an established target for AMPK, HER2, ERalpha, and Ki67 on Tissue Micro-Array (TMA) slides of two cohorts of 117 and 237 primary breast cancers. The quick score method was used for scoring and patterns of protein expression were compared with clinical and pathological data, including a minimum 5 years follow up.
  
  
  RESULTS
  Reduced signal, compared with the strong expression in normal breast epithelium, using a pAMPK antibody was demonstrated in 101/113 (89.4%) and 217/236 (91.9%) of two cohorts of patients. pACC was significantly associated with pAMPK expression (p = 0.007 & p = 0.014 respectively). For both cohorts, reduced pAMPK signal was significantly associated with higher histological grade (p = 0.010 & p = 0.021 respectively) and axillary node metastasis (p = 0.061 & p = 0.039 respectively). No significant association was found between pAMPK and any of HER2, ERalpha, or Ki67 expression, disease-free survival or overall survival.
  
  
  CONCLUSIONS
  This study extends in vitro evidence through immunohistochemistry to confirm that AMPK is dysfunctional in primary breast cancer. Reduced signalling via the AMPK pathway, and the inverse relationship with histological grade and axillary node metastasis, suggests that AMPK re-activation could have therapeutic potential in breast cancer.
authors.affiliation: Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee, UK. s.hadad@dundee.ac.uk
authors.forename: Sirwan M
authors.initials: SM
authors.lastname: Hadad
authors.forename: Lee
authors.initials: L
authors.lastname: Baker
authors.forename: Philip R
authors.initials: PR
authors.lastname: Quinlan
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Robertson
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bray
authors.forename: George
authors.initials: G
authors.lastname: Thomson
authors.forename: David
authors.initials: D
authors.lastname: Kellock
authors.forename: Lee B
authors.initials: LB
authors.lastname: Jordan
authors.forename: Colin A
authors.initials: CA
authors.lastname: Purdie
authors.forename: David G
authors.initials: DG
authors.lastname: Hardie
authors.forename: Stewart
authors.initials: S
authors.lastname: Fleming
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D055372:AMP-Activated Protein Kinases