The Significance of Microenvironmental and Circulating Lactate in Breast Cancer

Abstract

Lactate represents the main product of pyruvate reduction catalyzed by the lactic dehydrogenase family of enzymes. Cancer cells utilize great quantities of glucose, shifting toward a glycolytic metabolism. With the contribution of tumor stromal cells and under hypoxic conditions, this leads toward the acidification of the extracellular matrix. The ability to shift between different metabolic pathways is a characteristic of breast cancer cells and is associated with an aggressive phenotype. Furthermore, the preliminary scientific evidence concerning the levels of circulating lactate in breast cancer points toward a correlation between hyperlactacidemia and poor prognosis, even though no clear linkage has been demonstrated. Overall, lactate may represent a promising metabolic target that needs to be investigated in breast cancer.

Keywords: acidosis; aerobic glycolysis; breast cancer; lactate.

Figure 1

The reversible conversion of pyruvate into lactate catalyzed by LDH. The main isoforms (LDH-1, LDH-2, LDH-3, LDH-4, and LDH-5) are represented.

Figure 2

Lactate is produced starting from pyruvate in the cytosol (LDH-5 has the highest affinity for pyruvate). It can be transported through the mitochondrial membrane to serve as a fuel for TCA cycle. Lactate can be converted into pyruvate by the mitochondria-localized isoform (LDH-1). It may also be secreted through the plasma membrane into the extracellular matrix where it contributes to lactic acidosis.

Figure 3

Schematic representation of the interactions of the main constituent of TME with breast cancer cells. The hypoxic environment of breast cancer triggers the overexpression of HIF-1α, which fuels lactate production. These two lead to the overexpression of VEGF, promoting angiogenesis and tumor invasiveness. HIF-1α also leads to proinflammatory molecule secretion (like TNF-α, PGE, and IL1β) that sustains aromatase overexpression.