Recent studies have shown that energy metabolism in human pluripotent cells contrasts sharply with energy metabolism in differentiated cell types. Specifically, it has been shown that nuclear reprogramming from somatic cells to induced pluripotent stem cells is associated with a switch from oxidative to glycolytic metabolism. Whether a metabolic switch also occurs in reprogrammed/dedifferentiated breast cancer cells is unknown. Moreover, the function of the metabolic state in stemness is poorly understood and no data are available on whether breast cancer stem cells (CSCs) are metabolically different from committed cancer cells. Herein we demonstrated that HDAC inhibitors reprogram committed single aldefluor negative breast cancer cells into aldefluor positive cells (10.3 ± 2.8 vs 21.3 ±3.7% untreated vs treated P <0.05, representing an average of 5 single cell derived clones) and promoted tumor initiation from non-initiating committed cells (p = 0.004). Further, induced stem-like cells were resistant to taxol and salinomycin, a drug previously described to target CSCs. These reprogrammed cancer cells have enhanced activity of the pentose phosphate pathway (PPP) with upregulation of G6PD expression and activity and higher levels of NADPH and ROS. Hypothesizing that CSCs may favor the PPP in order to survive and self renew, we used G6PD inhibitors, 6-AN and Imatinib, to target mammosphere formation and aldefluor activity in HDAC inhibition induced stem-like cells. Not only was there a significant decrease in mammospheres from reprogrammed cells, the aldefluor activity was totally blocked at a concentration that does not affect proliferation. This work demonstrates that HDAC inhibition mediated cancer cell dedifferentiation promotes metabolic reprogramming and highlights an FDA approved drug that targets metabolism in stem cell plasticity. Further functional endpoint studies are underway to validate these findings.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-05.

2012