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

Cell Metab. 2017 Nov 7;26(5):778-787.e5. doi: 10.1016/j.cmet.2017.09.006. Epub 2017 Oct 5.

Abstract

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-1α compared with those that metastasize to the liver. PGC-1α promotes breast cancer cell migration and invasion in vitro and augments lung metastasis in vivo. Pro-metastatic capabilities of PGC-1α are linked to enhanced global bioenergetic capacity, facilitating the ability to cope with bioenergetic disruptors like biguanides. Indeed, biguanides fail to mitigate the PGC-1α-dependent lung metastatic phenotype and PGC-1α confers resistance to stepwise increases in metformin concentration. Overall, our results reveal that PGC-1α stimulates bioenergetic potential, which promotes breast cancer metastasis and facilitates adaptation to metabolic drugs.

Keywords: PGC-1α; breast cancer; metabolic flexibility; metabolomics; metastasis; metformin; mitochondria; phenformin; respirometry; seahorse.

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement
  • Energy Metabolism* / drug effects
  • Female
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Metabolomics
  • Metformin / pharmacology
  • Mice
  • Mice, SCID
  • Mitochondria / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*

Substances

  • Hypoglycemic Agents
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Metformin