PGC-1β regulates HER2-overexpressing breast cancer cells proliferation by metabolic and redox pathways

• Published in: Tumor biology Vol. 37; no. 5; pp. 6035 - 6044
• Main Authors: Victorino, Vanessa Jacob, Barroso, W. A., Assunção, A. K. M., Cury, V., Jeremias, I. C., Petroni, R., Chausse, B., Ariga, S. K., Herrera, A. C. S. A., Panis, C., Lima, T. M., Souza, H. P.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.05.2016
• Subjects: Aged; Biomedical and Life Sciences; Biomedicine; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer Research; Carrier Proteins - metabolism; Cell Line, Tumor; Cell Proliferation; Cell Survival - genetics; ERRalpha Estrogen-Related Receptor; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gene Silencing; Genes, erbB-2; Humans; Metabolic Networks and Pathways; Middle Aged; Neoplasm Grading; Neoplasm Staging; Original Article; Oxidation-Reduction; Reactive Oxygen Species; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; RNA, Small Interfering - genetics; RNA-Binding Proteins; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor Burden; PGC-1β; Proliferation; HER2- overexpressing; Breast cancer subtypes
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1007/s13277-015-4449-0

Breast cancer is a prevalent neoplastic disease among women worldwide which treatments still present several side effects and resistance. Considering that cancer cells present derangements in their energetic homeostasis, and that peroxisome proliferator-activated receptor- gamma coactivator 1 (PGC-1) is crucial for cellular metabolism and redox signaling, the main objective of this study was to investigate whether there is a relationship between PGC-1 expression, the proliferation of breast cancer cells and the mechanisms involved. We initially assessed PGC-1β expression in complementary DNA (cDNA) from breast tumor of patients bearing luminal A, luminal B, and HER2-overexpressed and triple negative tumors. Our data showed that PGC-1β expression is increased in patients bearing HER2-overexpressing tumors as compared to others subtypes. Using quantitative PCR and immunoblotting, we showed that breast cancer cells with HER2-amplification (SKBR-3) have greater expression of PGC-1β as compared to a non-tumorous breast cell (MCF-10A) and higher proliferation rate. PGC-1β expression was knocked down with short interfering RNA in HER2-overexpressing cells, and cells decreased proliferation. In these PGC-1β-inhibited cells, we found increased citrate synthase activity and no marked changes in mitochondrial respiration. Glycolytic pathway was decreased, characterized by lower intracellular lactate levels. In addition, after PGC-1β knockdown, SKBR-3 cells showed increased reactive oxygen species production, no changes in antioxidant activity, and decreased expression of ERRα, a modulator of metabolism. In conclusion, we show an association of HER2-overexpression and PGC-1β. PGC-1β knockdown impairs HER2-overexpressing cells proliferation acting on ERRα signaling, metabolism, and redox balance.