title: PGC-1β regulates HER2-overexpressing breast cancer cells proliferation by metabolic and redox pathways.
abstract: 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.
authors.affiliation: Laboratório de Investigação Médica - LIM 51, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil. vanjacob@gmail.com.
authors.forename: Vanessa Jacob
authors.initials: VJ
authors.lastname: Victorino
authors.affiliation: Laboratório de Investigação Médica - LIM 51, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: W A
authors.initials: WA
authors.lastname: Barroso
authors.affiliation: Laboratório de Investigação Médica - LIM 51, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: A K M
authors.initials: AK
authors.lastname: Assunção
authors.affiliation: Laboratório de Investigação Médica - LIM 51, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: V
authors.initials: V
authors.lastname: Cury
authors.affiliation: Laboratório de Investigação Médica - LIM 51, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: I C
authors.initials: IC
authors.lastname: Jeremias
authors.affiliation: Laboratório de Investigação Médica - LIM 51, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Petroni
authors.affiliation: Instituto de Química, Universidade de São Paulo (IQ-USP), São Paulo, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Chausse
authors.affiliation: Laboratório de Investigação Médica - LIM 51, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: S K
authors.initials: SK
authors.lastname: Ariga
authors.affiliation: Faculdade de Medicina, Pontifícia Universidade Católica, PUC, Campus Londrina, Paraná, Brazil.
authors.forename: A C S A
authors.initials: AC
authors.lastname: Herrera
authors.affiliation: Laboratório de Mediadores Inflamatórios, Universidade Estadual do Oeste do Paraná (UNIOESTE), Campus Francisco Beltrão, Paraná, Brazil.
authors.forename: C
authors.initials: C
authors.lastname: Panis
authors.affiliation: Laboratório de Investigação Médica - LIM 51, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: T M
authors.initials: TM
authors.lastname: Lima
authors.affiliation: Laboratório de Investigação Médica - LIM 51, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: H P
authors.initials: HP
authors.lastname: Souza
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D018734:Genes, erbB-2; D006801:Humans; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D002352:Carrier Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C455622:PPARGC1B protein, human
keywords: Breast cancer subtypes; HER2- overexpressing; PGC-1β; Proliferation