Metabolic fluxes can serve as specific biomarkers for detecting malignant transformations, tumor progression, and response to microenvironmental changes and treatment procedures. We present noninvasive hyperpolarized ¹³ C NMR investigations on the metabolic flux of pyruvate to lactate, in a well-controlled injection/perfusion system using T47D human breast cancer cells. Initial rates of pyruvate-to-lactate conversion were obtained by fitting the hyperpolarized ¹³ C and ancillary ³¹ P NMR data to a model, yielding both kinetic parameters and mechanistic insight into this conversion. Transport was found to be the rate-limiting process for the conversion of extracellular pyruvate to lactate with K _m = 2.14 ± 0.03 mM, typical of the monocarboxylate transporter 1 (MCT1), and a V _max = 27.6 ± 1.1 fmol·min ⁻¹ ·cell ⁻¹ , in agreement with the high expression level of this transporter. Modulation of the environment to hypoxic conditions as well as suppression of cells' perfusion enhanced the rate of pyruvate-to-lactate conversion, presumably by up-regulation of the MCT1. Conversely, the addition of quercetin, a flavonoidal MCT1 inhibitor, markedly reduces the apparent rate of pyruvate-to-lactate conversion. These results suggest that hyperpolarized ¹³ C ₁ -pyruvate may be a useful magnetic resonance biomarker of MCT regulation and malignant transformations in breast cancer.

Estrogen plays a key role in the development and progression of breast cancer; hence, antiestrogens, such as tamoxifen, have a marked impact on the treatment and outcome of breast cancer patients. Estrogen‐induced growth requires continuous replenishment of energy, predominantly generated by glycolysis. Previous work from this laboratory demonstrated estrogen induction and tamoxifen inhibition of glycolysis in MCF7 human breast cancer cells in vitro (Furman et al., J Steroid Biochem Mol Biol 1992;43:189–95). We present here studies of estrogen vs. tamoxifen regulation of glycolysis in orthotopic MCF7 human breast cancer xenografts in vivo. In addition we investigated mediation of this metabolic regulation through glucose transporter 1, in the same cells, in vitro, as well as in 2 other hormone‐responsive human breast cancer cells. Tumor response and glycolysis were monitored noninvasively by means of magnetic resonance imaging and ¹³C spectroscopy, respectively. During estrogen‐stimulated tumor growth (from ≈0.5 to ≈1.3 cm³ in 10 days), the rate of glucose metabolism through glycolysis in vivo was high at 40 ± 4 μmole/g/min. However, treatment for 10 days with tamoxifen induced growth arrest and a concomitant decrease of 2‐fold in the rate of glycolysis. In congruence, glucose transporter 1 expression was stimulated by estrogen, reaching after 72 hr a 2‐ to 3‐fold higher level of expression relative to that in tamoxifen‐treated cells. Thus, estrogen‐induced changes in glycolysis appeared to be mediated via its regulation of glucose transporter 1 expression. The in vivo monitoring of glycolysis may serve as a tool to expose hormonal regulation of glucose transporter 1 expression in breast cancer tumors, as well as to assess response to hormonal therapy.