title: The presence of Estrogen Receptor β modulates the response of breast cancer cells to therapeutic agents.
abstract: Breast cancer is a leading cause of death for women. The estrogen receptors (ERs) ratio is important in the maintenance of mitochondrial redox status, and higher levels of ERβ increases mitochondrial functionality, decreasing ROS production. Our aim was to determine the interaction between the ERα/ERβ ratio and the response to cytotoxic treatments such as cisplatin (CDDP), paclitaxel (PTX) and tamoxifen (TAM). Cell viability, apoptosis, autophagy, ROS production, mitochondrial membrane potential, mitochondrial mass and mitochondrial functionality were analyzed in MCF-7 (high ERα/ERβ ratio) and T47D (low ERα/ERβ ratio) breast cancer cell lines. Cell viability decreased more in MCF-7 when treated with CDDP and PTX. Apoptosis was less activated after cytotoxic treatments in T47D than in MCF-7 cells. Nevertheless, autophagy was increased more in CDDP-treated MCF-7, but less in TAM-treated cells than in T47D. CDDP treatment produced a raise in mitochondrial mass in MCF-7, as well as the citochrome c oxidase (COX) and ATP synthase protein levels, however significantly reduced COX activity. In CDDP-treated cells, the overexpression of ERβ in MCF-7 caused a reduction in apoptosis, autophagy and ROS production, leading to higher cell survival; and the silencing of ERβ in T47D cells promoted the opposite effects. In TAM-treated cells, ERβ-overexpression led to less cell viability by an increment in autophagy; and the partial knockdown of ERβ in T47D triggered an increase in ROS production and apoptosis, leading to cell death. In conclusion, ERβ expression plays an important role in the response of cancer cells to cytotoxic agents, especially for cisplatin treatment.
authors.affiliation: Grupo multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS-IdISPa), Universitat de les Illes Balears, E07122 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Spain.
authors.forename: Daniel Gabriel
authors.initials: DG
authors.lastname: Pons
authors.affiliation: Grupo multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS-IdISPa), Universitat de les Illes Balears, E07122 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Spain.
authors.forename: Margalida
authors.initials: M
authors.lastname: Torrens-Mas
authors.affiliation: Grupo multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS-IdISPa), Universitat de les Illes Balears, E07122 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Nadal-Serrano
authors.affiliation: Grupo multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS-IdISPa), Universitat de les Illes Balears, E07122 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Sastre-Serra
authors.affiliation: Grupo multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS-IdISPa), Universitat de les Illes Balears, E07122 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Spain. Electronic address: pilar.roca@uib.es.
authors.forename: Pilar
authors.initials: P
authors.lastname: Roca
authors.affiliation: Grupo multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS-IdISPa), Universitat de les Illes Balears, E07122 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Oliver
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D017382:Reactive Oxygen Species; D013629:Tamoxifen; D003576:Electron Transport Complex IV; D025261:Mitochondrial Proton-Translocating ATPases; D017239:Paclitaxel; D002945:Cisplatin
keywords: Breast cancer; ERα/ERβ ratio; Oxidative stress; ROS; Resistance