The Expression And Significance Of Glucose Transporter 1 And Nuclear Respiratory Factor 2 In Breast Carcinoma

【Background】Significant decrease in mitochondrial oxidative phosphorylation and dramatic increase in glycolysis are fundamental metabolism property of cancer cells. Breast cancer is the most common neoplasia among women in Europe and North America, with an estimated incidence of 7.6–9.1/10 000 inhabitants per year. Recent findings indicate that the abnormal expression of mitochondrial and glcolytic markers occurred significantly in breast carcinomas, as well as in other human cancers.Nuclear respiratory factors (NRFs), including to nuclear respiratory factors 1 (NRF-1) and 2 (NRF-2 / GABP), play a key role in coordinating the expression of a number of nuclear-encoded genes as well as several mitochondrial-encoded genes, involving mitochondrial oxidative respiration, cellular energy production and proliferation. In addition, NRF-2 also regulates genes that are intimately involved in cell cycle control, protein synthesis, and cellular metabolism. It has been reported that NRF-2 was uniquely bind to the proximal promoters of all ten nuclear-encoded COX subunit genes, it is a vital part of a molecular mechanism that senses upstream energy signals and modulates COX transcriptional levels in mammalian cells. Thus far, there is no any report on the regulation mechanism of NRF-2 to cellular energy metabolism on breast carcinoma.Glucose transporters (GLUTs) are membrane-embedded protein that mediates the uptake of glucose from the surrouding medium into the cell to fuel cells. They are significantly up-regulated in most of human solid tumors. Therefore, it is reasonable that the metabolic phenotype of the cell could provide markers for the analysis of cancer progression.【Objective】To study the expression and significance of Glut-1 and NRF-2 in breast carcinoma tissues, and to investigate the relationship of NRF-2 with the biological behavior of breast carcinoma.【Methods】A total of 147 cases of female breast tissue samples, including 92 cases of invasive breast ductal carcinoma, 26 cases of breast fibroadenoma, 24 cases of breast adenosis and 5 cases of normal breast tissues, were collected for quantitative detection of the expression of Glut-1 protein and mRNA by Dako EnVision immunohistochemistry, Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR). A total of 156 cases of female breast tissue samples, including 58 cases of invasive breast ductal carcinoma, 43 cases of breast fibroadenoma, 50 cases of breast adenosis and 5 cases of normal breast tissues, were collected for quantitative detection of the expression of NRF-2α/NRF-2βproteins and their mRNAs by Dako EnVision immunohistochemistry, Western blot and RT-PCR.【Results】: 1. In normal breast tissues and benign lesions of breast, Glut-1 was undetectable or only weakly detectable in cytoplasm of ductal and acinar epithelia. In contrast, the intensity of Glut-1 staining was significantly higher in invasive breast ductal carcinomas (p = 0.0002) with protein expression predominantly in cellular membrane and lesser in cytoplasm. Western blot and RT-PCR analyses showed that the expression of Glut-1 protein and mRNA were significantly increased in invasive breast ductal carcinoma than in fibroadenoma (p = 0.001 for protein; p < 0.05 for mRNA) and adenosis (p = 0.001 for protein; p < 0.05 for mRNA). There is a significantly difference among groups (p = 0.0002 for protein; p = 0.0001 for mRNA). 2. In normal breast tissues, benign lesions of breast and invastive breast ductal carcinomas, both NRF-2αand NRF-2βprotein were detectable in cellular nucleus and cytoplasm of ductal and acinar epithelia, especially in nucleus. The intensity of NRF-2αstaining was significantly higher in fibroadenoma when compare with adenosis (p = 0.0009) and invasive breast ductal carcinoma (p < 0.0001), the expression in adenosis is higer than in invasive breast ductal carcinoma (p = 0.0064). The intensity of NRF-2βstaining was significantly higher in fibroadenoma when compare with adenosis (p = 0.039) and invasive breast ductal carcinoma (p = 0.001). Western blot and RT-PCR analyses showed that there is no significantly difference among groups (p = 0.779 for protein; p = 0.322 for mRNA) for the expression of NRF-2α, and similar result for the expression of NRF-2βprotein (p = 0.275), but the expression of NRF-2βmRNA were significantly increased in invasive breast ductal carcinoma than in Non-carcinoma tissues (p = 0.016).【Conclusion】: Glucose transport activity, as indicated by Glut-1 protein and its mRNA, significantly increases in breast carcinoma than in breast non-cancerous lesions, the over-expression of Glut-1 in breast carcinoma is tightly coupled with tumor cell proliferation, invasion and metastasis, suggesting that Glut-1 may become a marker in the early diagnosis and prognosis of breast malignancy as well as a new therapeutic target. NRF-2, as a key regulator implicated in the coordinate regulation of nuclear components of the mitochondrial respiratory chain, has different expression in breast carcinoma and non-carcinoma lesions, which is probably associated with disturbance of tumor cellular energy metabolism. The regulation mechanism hasn't been reported until now, and further study is required.