Abstract
BackgroundAMP-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.MethodsImmunohistochemistry 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.ResultsReduced 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.ConclusionThis 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.
Highlights
AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge that responds to energy stress by suppressing cell growth and biosynthetic processes, ensuring that energyconsuming processes proceed only if there are sufficient metabolic resources
The objective of the present study was to evaluate the status of phosphorylation of Adeonsine Monophosphate Protein Kinase (AMPK) and Acetyl Coenzyme-A Carboxylase (ACC) signalling in human primary breast cancer using immunohistochemistry, and to correlate this with the clinical and pathological characteristics of the tumours
All cases were successfully scored for Ki67 and HER2; 3/117 (2.6%) for phospho-Acetyl Co-A Carboxylase (pACC), and 4/117 (3.4%) for pAMPK were not evaluable on the Tissue Micro-Array (TMA)
Summary
AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge that responds to energy stress by suppressing cell growth and biosynthetic processes, ensuring that energyconsuming processes proceed only if there are sufficient metabolic resources. AMP-activated protein kinase (AMPK) is an intracellular energy-sensing kinase that is inactive unless it has been phosphorylated by upstream kinases at a specific threonine residue (Thr-172) within the kinase domain. Phosphorylation at Thr-172 and consequent activation occurs in response to metabolic stresses that deplete cellular energy levels and increase the AMP/ATP ratio [1,2]. AMPK down-regulates energy-consuming processes, including cell proliferation, ensuring that these processes only proceed if there are sufficient metabolic resources available [8]. AMPK switches on catabolic pathways that generate ATP, while switching off biosynthetic pathways and other processes that consume ATP, and has a key role in maintaining energy balance both at the single cell and the whole body levels [2,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
