The Metabolic Mechanisms of Breast Cancer Metastasis

Abstract

Breast cancer is one of the most common malignancy among women worldwide. Metastasis is mainly responsible for treatment failure and is the cause of most breast cancer deaths. The role of metabolism in the progression and metastasis of breast cancer is gradually being emphasized. However, the regulatory mechanisms that conduce to cancer metastasis by metabolic reprogramming in breast cancer have not been expounded. Breast cancer cells exhibit different metabolic phenotypes depending on their molecular subtypes and metastatic sites. Both intrinsic factors, such as MYC amplification, PIK3CA, and TP53 mutations, and extrinsic factors, such as hypoxia, oxidative stress, and acidosis, contribute to different metabolic reprogramming phenotypes in metastatic breast cancers. Understanding the metabolic mechanisms underlying breast cancer metastasis will provide important clues to develop novel therapeutic approaches for treatment of metastatic breast cancer.

Keywords: breast cancer; glycolysis; hypoxia; metabolic phenotypes; metabolism; metastasis; molecular mechanisms.

Figure 1

Metabolic pathways in breast cancer cells. Breast cancer cells enhance metabolism of glucose, amino acid lipid by regulating multiple metabolic pathways. Breast tumor cells mainly use aerobic glycolysis to produce ATP and utilize the pentose phosphate pathway to produce macromolecules such as NADPH. Wild-type and mutant P53 have contrary effects in monitoring fatty acid metabolism. Hypoxia, acidosis and ROS are regarded as important events which influence multiple metabolic pathways.

Figure 2

Metabolic reprogramming in the metastatic cascade. Metabolic reprogramming occurs at several steps of metastasis. The intravasation of cells from the primary tumor is promoted by extracellular acidification. CTCs survive in oxidative stress by producing NADPH and GSH. Cancer cells show different metabolic characteristics based on the sites which they metastasize. Last, anabolic metabolism is reactivated during macro-metastatic tumor proliferation.