Glucose uptake by tumors is stimulated by estradiol (E2) administration in estrogen receptor positive (ER+) breast cancer patients. Notably, this E2-induced metabolic flare is predictive of the clinical effectiveness of anti-estrogens and, therefore, downstream metabolic regulators of E2 are expected to have utility as anti-breast cancer agents. Although 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. We have demonstrated that the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key regulator of the glycolytic flux, is elevated in breast cancer lymph node metastases and that exposure of ER+ 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, fructose-2,6-bisphosphate (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 In unpublished results, we demonstrated that the combination of the anti-estrogen, fulvestrant, with PFK158 results in greater regressions of MCF-7 xenografts than either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 decrease in tumor cell growth. We found that exposure of breast cancer cells to palbociclib and PFK158 causes a synergistic increase in cell cycle arrest and apoptotic cell death. In addition, we observed a synergistic decrease in phospho-retinoblastoma protein (Rb), a key downstream target of CDK4/6. Importantly, we found that the combination of PFK158 and palbociclib did not cause an increase in cell cycle arrest or apoptosis 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, Amy Clem, Brian Clem, Gilles Tapolsky, Sucheta Telang, Jason Chesney. Suppression of 6-Phosphofructo-2-Kinase (PFKFB3) for the treatment of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 56.