PGC-1α Promotes Breast Cancer Metastasis and Confers Bioenergetic Flexibility against Metabolic Drugs

Metabolic adaptations play a key role in fueling tumor growth. However, less is known regarding the metabolic changes that promote cancer progression to metastatic disease. Herein, we reveal that breast cancer cells that preferentially metastasize to the lung or bone display relatively high expression of PGC-1 alpha compared with those that metastasize to the liver. PGC-1 alpha promotes breast cancer cell migration and invasion in vitro andaugments lung metastasis in vivo. Pro-metastatic capabilities of PGC-1 alpha are linked to enhanced global bioenergetic capacity, facilitating the ability to cope with bioenergetic disruptors like biguanides. Indeed, biguanides fail to mitigate the PGC-1 alpha-dependent lung metastatic phenotype and PGC-1 alpha confers resistance to stepwise increases in metformin concentration. Overall, our results reveal that PGC-1 alpha stimulates bioenergetic potential, which promotes breast cancer metastasis and facilitates adaptation to metabolic drugs.