Abstract A84: Regulation of 6-phosphofructo-2-kinase (PFKFB3) by estradiol and implications for the treatment of ER+ metastatic breast cancer
| العنوان: | Abstract A84: Regulation of 6-phosphofructo-2-kinase (PFKFB3) by estradiol and implications for the treatment of ER+ metastatic breast cancer |
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| المؤلفون: | Jason Chesney, Gilles Tapolsky, Brian F. Clem |
| المصدر: | Molecular Cancer Research. 14:A84-A84 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Cancer Research, biology, Fulvestrant, Glucose uptake, Estrogen receptor, Cancer, Palbociclib, medicine.disease, Metastatic breast cancer, Breast cancer, Oncology, Cyclin-dependent kinase, medicine, biology.protein, Cancer research, Molecular Biology, medicine.drug |
| الوصف: | Estradiol (E2) administered to estrogen receptor positive (ER+) breast cancer patients stimulates glucose uptake by tumors. This E2-induced metabolic flare is predictive of the clinical effectiveness of anti-estrogens and downstream metabolic regulators of E2 are expected to have utility as targets for the development of anti-breast cancer agents. While the stimulation of glucose metabolism by E2 has been demonstrated, relatively little is known about the precise downstream effectors required for E2 to stimulate glucose metabolism in breast cancer. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) control glycolytic flux via their product, fructose-2,6-bisphosphate (F26BP), which activates 6-phosphofructo-1-kinase (PFK-1). We recently demonstrated that PFKFB3 expression is elevated in breast cancer lymph node metastases and that exposure of human MCF-7 and T-47D breast cancer cells to E2 causes a rapid increase in 14C-glucose uptake and glycolysis that is coincident with an induction of PFKFB3 mRNA (via ER binding to its promoter), protein expression and the intracellular concentration of its product, F26BP. Importantly, we also found that selective inhibition of PFKFB3 expression and activity using siRNA or a PFKFB3 inhibitor, PFK158, markedly reduces the E2-mediated increase in F26BP, 14C-glucose uptake and glycolysis. In the current study, we sought to determine if co-administration of PFK158, with ICI 182,780 (fulvestrant), would offer a greater anti-tumor effect. In unpublished results, we demonstrated that the combination of the anti-estrogen, fulvestrant, with PFK158 results in greater regressions of MCF-7 xenografts than either drug alone in athymic BALB/C mice. In addition to regulating glucose metabolism, PFKFB3 has been found to be a regulator of the cell cycle via cyclin dependent kinases. We postulated that the combination of PFK158 with the newly FDA-approved CDK4/6 inhibitor palbociclib may result in a synergistic increase in apoptosis. We found that PFK158 markedly increased apoptosis caused by palbociclib in MCF-7 breast cancer cells but not in normal human mammary epithelial cells. Taken together, these data indicate that PFKFB3 inhibitors such as PFK158 may have clinical utility for the treatment of ER+ breast cancers when combined with anti-estrogen agents and/or CDK4/6 inhibitors. Citation Format: Yoannis Imbert-Fernandez, Brian Clem, Gilles Tapolsky, Jason Chesney. Regulation of 6-phosphofructo-2-kinase (PFKFB3) by estradiol and implications for the treatment of ER+ metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A84. |
| تدمد: | 1557-3125 1541-7786 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::4269115e2126b9802e9f8b1c35110c9eTest https://doi.org/10.1158/1557-3125.metca15-a84Test |
| رقم الانضمام: | edsair.doi...........4269115e2126b9802e9f8b1c35110c9e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573125 15417786 |
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