Glycolysis and glucose transporter 1 as markers of response to hormonal therapy in breast cancer

Abstract

Cancer cells utilize glucose as their main energy source and convert it to lactate at high rates, even in the presence of high oxygen concentrations. 1 Previous studies have indicated that the enhanced rate of glucose uptake in tumors might be related to an overexpression of the facilitated glucose transporter proteins. 2,3 Further studies of inducing malignant transformation of fibroblast cells by transfection with ras or src demonstrated upregulation of the glucose transporters as well. 4,5 More recently transformation of cells by c-myc transfection of rat fibroblasts showed specific induction of the glucose transporter 1 (GLUT1) expression. 6 Enhanced glycolysis and high expression of the glucose transporters were specifically identified in human breast cancer cells. [7][8][9][10][11] In addition, the expression of GLUT1 was found to be a characteristic feature in breast cancer biopsies, with a positive correlation between this expression and tumor grade, extent of proliferation and invasiveness. [12][13][14][15][16] Recently, Kang et al. 17 investigated the clinical significance of GLUT1 expression in human breast carcinoma and found a significant correlation between GLUT1 expression and estrogen and progesterone receptor status. These results are in accord with studies of human breast cancer cells in vitro, where induction of cellular differentiation of human breast cancer cells resulted in decreased expression of protein GLUT1. 9 The above findings emphasize that malignant transformation is involved in the deregulation of the expression of the glucose transporters and consequently the augmentation of glucose metabolism and glycolysis.A large number of breast tumors express receptors for estrogen, which regulates various cellular activities by modulating metabolism in the course of tumor growth and progression. 18,19 The estrogen receptors (ER ␣ and ␤), which are ligand-dependent transcription factors, 20 play a key role in the development and progression of breast cancer, as well as in the treatment of breast cancer patients. 21 Tamoxifen, the leading antiestrogenic drug, has been proven to be effective in improving overall survival in both pre-and postmenopausal women. 22 Furthermore, tamoxifen also has been shown to reduce cancer incidence and prevent new tumor formation and growth. 23 Estrogen binding to its receptor induces critical metabolic and physiologic activities via activating various ER-responsive genes. Specifically, estrogen was shown to stimulate glucose metabolism and glycolysis in various target organs, including the uterus-the classic estrogen target organ. 24,25 Furthermore, in the uterus and primate cerebral cortex, it was found that estrogen regulation of glycolysis is mediated by altering the expression levels of GLUT1. 26,27 In breast cancer, kinetic studies of perfused cells in vitro have demonstrated induction of glycolysis by estrogen and its inhibition by tamoxifen. 7,8 The prevalent role of estrogen in breast cancer progression and the need for developing objective surrogate ma...

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

“…The mechanism of this effect is thought to be via the estrogen receptor (ER), as cells treated with the ER antagonist tamoxifen had lower rates of glucose consumption compared to E 2 -treated cells (Neeman and Degani, 1989). A recent study by the same group found that estrogen-induced changes in glycolysis in orthotopic MCF-7 human breast cancer xenografts appear to be mediated by regulation of GLUT1 expression (Rivenzon-Segal et al, 2003).…”

Proteomic Analysis of Potential Breast Cancer Biomarkers

“…Proteomic analysis also reveals that proteins involved in carbohydrate metabolism are significantly over-expressed in MCF-7 cells ( Figure 9C). This demonstrates that cancer cells rely heavily on glycolysis to obtain ATP for proliferation and tumorigenesis in the presence www.intechopen.com of adequate oxygen levels (Lopez-Lazaro, 2008); this mechanism has been implicated in numerous cancer therapies (Gatenby and Gillies, 2007;Rivenzon-Segal et al, 2003). Figures 9D~F show the downregulated profiles of proteins in both MCF-7 and MDA-MB-231 cells.…”

Glucose Metabolism in Breast Cancer and its Implication in Cancer Therapy

“…Moreover, in mouse mammary tumor cells, the insulin receptor substrate (IRS), which was shown to be involved in breast cancer invasion, survival and metastasis, could promote tumor invasion through GLUT1-mediated sustainment of aerobic glycolysis [129]. Furthermore, cellular oncogene c-myc, protein kinase Akt, and ovarian hormone estrogen are also known to induce GLUT1 expression [130][131][132][133]. In addition, it has been demonstrated that GLUT3 expression and glucose uptake can be up-regulated through secondary messenger cAMP pathway in breast cancer cell line ZR-75 [122].…”

“…These changes were consistent with the observed downregulation of GLUT1 expression. Thus, it is proposed that in vivo monitoring of glycolysis may function as a tool to reveal hormonal regulation of GLUT1 expression in breast cancer tumors, as well as to assess tumor response to hormonal therapy [133]. In addition to estrogen, GLUTs expression correlates well with estrogen recaptors (ER) expression level, especially ER-alpha [135].…”