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<p>Tamoxifen resistance development in breast cancer cells is a major clinical challenge. Metabolic alterations play a fundamental role in cancer progression as well as drug resistance development. Understanding alterations in the extracellular metabolites’ concentrations and their correlation with transporter gene expression in MCF-7 cells resistant to tamoxifen may provide insight into adaptive resistance mechanisms. In the present study, a validated LC-MS/MS method and real-time PCR were employed to correlate the changes in the concentrations of glutamate, glutamine, cystine, glutathione and xanthine in MCF-7 tamoxifen-resistant cells’ supernatant media with the altered gene expression levels of the metabolites’ transporters. Gene expression levels of the studied genes were then correlated to the overall survival of breast cancer patients from different databases. Excellent linearity (R<sup>2</sup>= 0.9998, 0.9998, 0.9969, 0.9989, and 0.9991) and high sensitivity with LOD values of 1, 20, 10, 0.5, and 0.2&#xa0;mg/L and LOQ values of 10, 200, 100, 5 and 2&#xa0;mg/L were obtained for glutamate, glutamine, cystine, glutathione, and xanthine, respectively. Excellent inter- and intra-day accuracy results and percent recovery were obtained in the range of 93.2% − 98.4% and 95.40% – 104.64%, respectively, and precision values obtained were in the range of 0.174–1.363%RSD. The acquired resistance to tamoxifen on the cellular level of MCF-7 cells has altered the concentrations of glutamate, glutamine, cystine, glutathione, and xanthine in the extracellular media of tamoxifen-resistant MCF-7 cells. Reduced expression of <i>SLC1A1</i>and <i>SLC1A2</i> may contribute to the altered glutamate metabolism observed in tamoxifen-resistant cells, while reduced expression of <i>SLC7A11</i> may contribute to the altered cystine and glutamate metabolism observed in these cells. In addition, decreased expression levels of <i>SLC2A9</i> may contribute to the altered xanthine metabolism observed in the tamoxifen -resistant cells. Poor overall survival among breast cancer patients was found to be correlated with the down regulation of these genes’ expression. The findings obtained may contribute to a better understanding of the mechanisms of tamoxifen resistance and may help in identifying biomarkers of tamoxifen resistance.</p>

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Extracellular levels of glutamate, glutamine, cystine, glutathione, and xanthine correlate with transporter expression in tamoxifen - resistant MCF-7 cells and poor overall survival in breast cancer patients

  • 期刊论文

  • 发表日期：

    2026年3月16日

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  • Ala A. Alhusban,
  • Lama A. Hamadneh,
  • Mohammad Alwahsh,
  • Mays E. Altaweel,
  • Ola A. Tarawneh,
  • Wassan Jarrar,
  • Ahmad A. Deeb,
  • Aya Hasan

摘要

Tamoxifen resistance development in breast cancer cells is a major clinical challenge. Metabolic alterations play a fundamental role in cancer progression as well as drug resistance development. Understanding alterations in the extracellular metabolites’ concentrations and their correlation with transporter gene expression in MCF-7 cells resistant to tamoxifen may provide insight into adaptive resistance mechanisms. In the present study, a validated LC-MS/MS method and real-time PCR were employed to correlate the changes in the concentrations of glutamate, glutamine, cystine, glutathione and xanthine in MCF-7 tamoxifen-resistant cells’ supernatant media with the altered gene expression levels of the metabolites’ transporters. Gene expression levels of the studied genes were then correlated to the overall survival of breast cancer patients from different databases. Excellent linearity (R2= 0.9998, 0.9998, 0.9969, 0.9989, and 0.9991) and high sensitivity with LOD values of 1, 20, 10, 0.5, and 0.2 mg/L and LOQ values of 10, 200, 100, 5 and 2 mg/L were obtained for glutamate, glutamine, cystine, glutathione, and xanthine, respectively. Excellent inter- and intra-day accuracy results and percent recovery were obtained in the range of 93.2% − 98.4% and 95.40% – 104.64%, respectively, and precision values obtained were in the range of 0.174–1.363%RSD. The acquired resistance to tamoxifen on the cellular level of MCF-7 cells has altered the concentrations of glutamate, glutamine, cystine, glutathione, and xanthine in the extracellular media of tamoxifen-resistant MCF-7 cells. Reduced expression of SLC1A1and SLC1A2 may contribute to the altered glutamate metabolism observed in tamoxifen-resistant cells, while reduced expression of SLC7A11 may contribute to the altered cystine and glutamate metabolism observed in these cells. In addition, decreased expression levels of SLC2A9 may contribute to the altered xanthine metabolism observed in the tamoxifen -resistant cells. Poor overall survival among breast cancer patients was found to be correlated with the down regulation of these genes’ expression. The findings obtained may contribute to a better understanding of the mechanisms of tamoxifen resistance and may help in identifying biomarkers of tamoxifen resistance.