Original articleHigh expressions of LDHA and AMPK as prognostic biomarkers for breast cancer
Introduction
Breast cancer is one of the highest incidences of cancers in women worldwide and is the first and second cause of cancer death among women in more developed and less developed countries, respectively. It is estimated that there were 1,676,600 new cases and 521,900 deaths of breast cancers in women worldwide in 2012 [1]. According to its molecular subtype, breast cancer is classified into different categorizations, including luminal A, luminal B, Her-2 neu and basal like subtypes. Among them, the prognosis of triple-negative breast cancer (TNBC) patients remains poor. And there is still lack of effective diagnostic and prognostic markers for TNBC [2].
Reprogramming of metabolism is very common in cancer cells. Due to the Warburg effect, cancer cells increase metabolic intermediates to better support rapid cell growth [3]. Aberrant tumor metabolism has been proved to help the progression and metastasis of tumors [4]. A series of enzymes have been identified to play vital roles in regulation of Warburg effect. Among them, lactate dehydrogenase A (LDHA) and AMP-activated protein kinase (AMPK) have been reported to be of great importance in tumor metabolism [5], [6], [7]. It's been reported that LDHA is commonly up-regulated and is correlated with worse survival outcomes of many cancers [8], [9], [10], [11], [12]. We previously found a high expression of LDHA in breast cancer, which was associated with worse clinical outcomes [13]. As for AMPK, its dysfunction has recently been highlighted in several cancers, including breast cancer [14], [15]. In our previous study we found that AMPK was significantly up-regulated in breast cancer cell lines and tissues and predicted shorter OS and DFS [16]. What's more, increasing number of researches show that LDHA and AMPK promoted glycolysis and cell proliferation in cancers [8], [9], [11], [12], [15], [16]. These findings indicate that LDHA and AMPK could be prognostic factors and therapeutic targets in breast cancer patients.
In this study, we explored the expression pattern of LDHA and AMPK in breast cancer, especially in TNBC. Then we investigated the prognostic roles of LDHA and AMPK in breast cancer patients. Our study provides evidence that LDHA and AMPK could be prognostic factors and potential therapeutic targets in breast cancer, especially in TNBC.
Section snippets
Materials and methods
This study was conceived and presented with regard to the reporting recommendations for tumor marker prognostic studies (REMARK) guidelines [17].
LDHA and AMPK were up-regulated synchronously in breast cancer
To explore the expression pattern of LDHA and AMPK in breast cancer, Western blot and qRT-PCR were performed. Expression of LDHA and AMPK were detected in four NTNBC cell lines and four TNBC cell lines. The result showed that LDHA and AMPK were up-regulated synchronously in breast cancer cell lines, especially in TNBC cell lines (Fig. 1A and B). Similarly, both LDHA and AMPK were up-regulated in TNBC tissues compared to NTNBC tissues (Fig. 1C and D).
The expression of LDHA and AMPK showed a positive correlation in breast cancer
The expression of LDHA and AMPK were further
Discussion
Tumor metabolism has long been researched and recently it has been intensely discussed [22]. The importance of aberrant tumor metabolism has been highlighted in more and more researches. Genetic events in cancer such as activated oncogenes or loss of cancer suppressors could activate signaling pathways, leading to altered metabolism in cancer cells. Aerobic glycolysis or the Warburg effect is a common feature of cancer and is reported to provide energy and materials for cancer proliferation and
Conclusions
In summary, this study demonstrated that LDHA and AMPK were up-regulated synchronously in breast cancer, especially in TNBC, which was associated with poor clinical outcomes. Our findings provide significant evidence that LDHA and AMPK could be prognostic factors and potential therapeutic targets in breast cancer, especially in TNBC. Detecting and targeting LDHA and AMPK at the same time should be recommended in clinical management of breast cancer.
Ethics statement
All procedures performed in this study involving human participants were approved by Ethics Committees of Sun Yat-Sen University Cancer Center and were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent about the researchable use of the clinical data was obtained from each participant patient. All patient data were anonymous and de-identified prior to analysis.
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (81472575, 81472469 and 81272514) and the Science and Technology Planning Projects of Guangdong and Guangzhou (2013B060300009, 2015B020211002, 2015B090901050 and 2014A020212079).
References (40)
- et al.
Cancer's sweet tooth
Cancer Cell
(2006) - et al.
Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer
Cancer Cell
(2013) - et al.
The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator
Cancer Lett
(2015) - et al.
A combined proteomics and metabolomics profiling of gastric cardia cancer reveals characteristic dysregulations in glucose metabolism
Mol Cell Proteom
(2010) - et al.
Degradation of AMPK by a cancer-specific ubiquitin ligase
Cell
(2015) - et al.
Endocrine-related cancers and the role of AMPK
Mol Cell Endocrinol
(2013) - et al.
The Warburg effect and mitochondrial stability in cancer cells
Mol Asp Med
(2010) - et al.
AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism
Cell Metab
(2005) - et al.
AMPK and autophagy in glucose/glycogen metabolism
Mol Asp Med
(2015) - et al.
The impact of phosphorylated AMP-activated protein kinase expression on lung cancer survival
Ann Oncol
(2012)
Global cancer statistics
CA Cancer J Clin
Triple-negative breast cancer
N Engl J Med
Understanding the Warburg effect: the metabolic requirements of cell proliferation
Science
A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer
Clin Cancer Res
FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression
Clin Cancer Res
Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma
Mol Cancer
LDHA is necessary for the tumorigenicity of esophageal squamous cell carcinoma
Tumor Biol
Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer
Oncotarget
The miR-34a-LDHA axis regulates glucose metabolism and tumor growth in breast cancer
Sci Rep UK
mir-101-3p is a key regulator of tumor metabolism in triple negative breast cancer targeting AMPK
Oncotarget
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These authors contributed equally to this work.