Differential Site-Based Expression of Pentose Phosphate Pathway-Related Proteins among Breast Cancer Metastases

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MeSH: Aged ; Bone Neoplasms/secondary ; Bone and Bones/pathology ; Brain Neoplasms/secondary ; Breast Neoplasms/metabolism* ; Breast Neoplasms/pathology* ; Carboxylic Ester Hydrolases/metabolism ; Carcinoma, Ductal, Breast/metabolism* ; Cytoplasm/metabolism ; Female ; Gene Expression Regulation, Neoplastic* ; Humans ; Ki-67 Antigen/metabolism ; Liver Neoplasms/secondary ; Lung Neoplasms/secondary ; Middle Aged ; NF-E2-Related Factor 2/metabolism* ; Neoplasm Metastasis ; Pentose Phosphate Pathway* ; Phenotype ; Phosphogluconate Dehydrogenase/metabolism ; Prognosis ; Proportional Hazards Models ; Receptor, ErbB-2/metabolism ; Risk Factors ; Tissue Array Analysis ; Treatment Outcome

Abstract: Purpose : We aimed to investigate the expression of pentose phosphate pathway- (PPP-) related proteins in metastatic breast cancer and its relationship with clinicopathologic factors.

Methods : Tissue samples from 126 metastatic breast cancers were included in a tissue microarray. Expression of PPP-related proteins [glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconolactonase (6PGL), 6-phosphogluconate dehydrogenase (6PGDH), and nuclear factor erythroid 2-related factor (NRF2)] was determined by immunohistochemistry. Results. G6PDH (p = 0.011) and cytoplasmic NRF2 (p = 0.001) showed the highest expression in brain metastases. Human epidermal growth factor receptor (HER-2) positivity was associated with G6PDH (p < 0.001) and cytoplasmic NRF2 (p = 0.015) positivity. A high Ki-67 labeling index (LI) was correlated with nuclear NRF2 positivity (p = 0.037), and HER-2-positive luminal B type was associated with G6PDH positivity (p = 0.001). On multivariate Cox analysis, independent risk factors of short overall survival were 6PGL positivity in bone metastasis (HR 4.180, 95% CI 1.160-15.06, p = 0.029) and low Ki-67 LI in lung metastasis (HR 11.853, 95% CI 1.841-76.30, p = 0.009).

Conclusion : Differential expression of PPP-related proteins correlated with different prognoses and metastatic sites, with the highest expression in brain metastases, and could be a potential therapeutic target.