Mitochondrial HER2 stimulates respiratory chain function and drives tumorigenicity of breast cancer cells

Abstract

Amplification of HER2/ERBB2, a breast cancer oncogene, leads to resistance to therapy and poor prognosis in breast cancer patients. HER2, a member of the EGFR protein family, normally localizes to the plasma membrane. Recently, a fraction of HER2 has been reported at the inner mitochondrial membrane, where it interacts with the respiratory chain. Now we show that overexpression of mitochondrial HER2 (mtHER2) stimulates respiratory chain function in breast cancer cells in a tyrosine kinase‐dependent manner. Moreover, overexpression of mtHER2 increases proliferation, migration and reactive oxygen species production. Interestingly, mtHER2 makes the cells prone to treatment with mitochondria‐targeted tamoxifen (MitoTam), a new respiratory complex I inhibitor now in clinical trials. Therefore, mtHER2 affects both tumorigenicity and sensitivity to treatment by regulating mitochondrial bioenergetics and represents therefore a new treatment opportunity in HER2 high breast cancer.