title: Steroidal aromatase inhibitors inhibit growth of hormone-dependent breast cancer cells by inducing cell cycle arrest and apoptosis.
abstract: Different hormonal therapies are used for estrogen receptor positive (ER(+)) breast cancers, being the third-generation of aromatase inhibitors (AIs), an effective alternative to the classical tamoxifen. AIs inhibit the enzyme aromatase, which is responsible for catalyzing the conversion of androgens to estrogens. In this study, it was evaluated the effects of several steroidal AIs, namely 3β-hydroxyandrost-4-en-17-one (1), androst-4-en-17-one (12), 4α,5α-epoxyandrostan-17-one (13a) and 5α-androst-2-en-17-one (16), on cell proliferation, cell cycle progression and cell death in an ER(+) aromatase-overexpressing human breast cancer cell line (MCF-7aro). All AIs induced a decrease in cell proliferation and these anti-proliferative effects were due to a disruption in cell cycle progression and cell death, by apoptosis. AIs 1 and 16 caused cell cycle arrest in G0/G1, while AIs 12 and 13a induced an arrest in G2/M. Moreover, it was observed that these AIs induced apoptosis by different pathways, since AIs 1, 12 and 13a activated the apoptotic mitochondrial pathway, while AI 16 induced apoptosis through activation of caspase-8. These results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer cells and will also highlight the importance of AIs as inducers of apoptosis in hormone-dependent breast cancers.
authors.affiliation: Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, no. 228, 4050-313, Porto, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Amaral
authors.affiliation: Pharmaceutical Chemistry Group, CEF, Center for Pharmaceutical Studies, Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Varela
authors.affiliation: Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, no. 228, 4050-313, Porto, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Borges
authors.affiliation: Pharmaceutical Chemistry Group, CEF, Center for Pharmaceutical Studies, Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
authors.forename: Elisiário
authors.initials: E
authors.lastname: Tavares da Silva
authors.affiliation: Pharmaceutical Chemistry Group, CEF, Center for Pharmaceutical Studies, Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
authors.forename: Fernanda M F
authors.initials: FMF
authors.lastname: Roleira
authors.affiliation: Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, no. 228, 4050-313, Porto, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.
authors.forename: Georgina
authors.initials: G
authors.lastname: Correia-da-Silva
authors.affiliation: Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, no. 228, 4050-313, Porto, Portugal. natercia@ff.up.pt.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal. natercia@ff.up.pt.
authors.forename: Natércia
authors.initials: N
authors.lastname: Teixeira
mesh_terms: D000736:Androstenes / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000736:Androstenes; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D011960:Receptors, Estrogen; D053181:Caspase 8