Research article

Histological evaluation of AMPK signalling in primary breast cancer

Sirwan M Hadad¹ , Lee Baker¹ , Philip R Quinlan¹ , Katherine E Robertson² , Susan E Bray¹ , George Thomson² , David Kellock¹ , Lee B Jordan² , Colin A Purdie² , David G Hardie³ , Stewart Fleming² and Alastair M Thompson¹

¹  Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee, UK

²  Department of Pathology and Neuroscience, Ninewells Hospital and Medical School, Dundee, UK

³  Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, UK

author email corresponding author email

BMC Cancer 2009, 9:307doi:10.1186/1471-2407-9-307

Published:	1 September 2009

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, ERα, 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, ERα, or Ki67 expression, disease-free survival or overall survival.

Conclusion

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.