Glycometabolism is a distinctive aspect of energy metabolism in breast cancer, and key glycometabolism enzymes/pathways (glycolysis, hexosamine biosynthetic pathway, and pentose phosphate pathway) may directly or indirectly affect the clinical features. In this study, we analyzed the particular correlation between the altered glycometabolism and clinical features of breast cancer to instruct research and clinical treatment. Tissue microarrays containing 189 hollow needle aspiration samples and 295 triple-negative breast cancer tissues were used to test the expression of M2 isoform of pyruvate kinase (PKM2), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose-6-phosphate dehydrogenase (G6PD), and p53 by immunohistochemistry and the intensity of these glycometabolism-related protein was evaluated. Chi-square test, Kaplan-Meier estimates, and Cox proportional hazards model were used to analyze the relationship between the expression of these factors and major clinical features. PKM2, GFPT1, and G6PD affect the pathologic complete response rate of neoadjuvant chemotherapy patients in different ways; pyruvate kinase muscle isozyme 2 (PKM2) and G6PD are closely associated with the molecular subtypes, whereas GFPT1 is correlated with cancer size. All these three factors as well as p53 have impacts on the progression-free survival and overall survival of triple-negative breast cancer patients. Cancer size shows significant association with PKM2 and GFPT1 expression, while the pN stage and grade are associated with PKM2 and G6PD expression. Our study support that clinical characteristics are reflections of specific glycometabolism pathways, so their relationships may shed light on the orientation of research or clinical treatment. The expression of PKM2, GFPT1, and G6PD are hazardous factors for prognosis: high expression of these proteins predict worse progression-free survival and overall survival in triple-negative breast cancer, as well as worse pathologic complete response rate in neoadjuvant chemotherapy breast cancer. However, p53 appears as a protective factor only in the patients receiving neoadjuvant chemotherapy. All the four proteins, PKM2, GFPT1, G6PD and p53, are prognostic markers of breast cancer. The correlation among them suggests that there may be crosstalk of the four proteins in breast cancer.
Breast cancer Neoadjuvant chemotherapy Glycolysis Pentose phosphate pathway Hexosamine biosynthetic pathway Prognostic and predictive value
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This study was supported by grant YJSCX2014-49HYD from Harbin Medical University, Harbin, China, The Department of Medical Oncology of the Third Affiliated Hospital of Harbin Medical University, Harbin, China, and the Tumor Research Institute of Heilongjiang, Harbin, China.
Tieying Dong performed IHC experiments, wrote the manuscript, prepared the figures, participated in study design, and interpretation of data. Qijia Xuan prepared the figures and tables. Wenjie Ma collected the information of patients enrolled in this study. Xinmei Kang developed microscopy tools, analyzed specimens, and made a significant contribution to the study design and interpretation of data. Zhaoliang Liu revised the manuscript and polished the language. Shu Zhao and Hang Liu made substantial contributions to review the IHC specimens independently. Zhipeng Wang was involved in critical revisions to the manuscript for important intellectual content. Dr. Qingyuan Zhang participated in the experiment design and interpretation of data. Dr. Qingyuan Zhang gave final approval of the manuscript version to be published and agree to be accountable for questions related to any part of the work. All authors have critically read, edited, and approved the final version of the manuscript.
Compliance with ethical standards
This study was conducted with approval from the Ethics Committee of the Third Affiliated Hospital of Harbin Medical University.
Supplementary FigureThe percentages of positive expression of PKM2, GFPT1, and G6PD in breast cancer group is significantly different from those in relative healthy control group. (PNG 176 kb)
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