title: FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance.
abstract: Drug resistance is a major hurdle for successful treatment of breast cancer, the leading cause of deaths in women throughout the world. The FOXM1 transcription factor is a potent oncogene that transcriptionally regulates a wide range of target genes involved in DNA repair, metastasis, cell invasion, and migration. However, little is known about the role of FOXM1 in cell survival and the gene targets involved. Here, we show that FOXM1-overexpressing breast cancer cells display an apoptosis-resistant phenotype, which associates with the upregulation of expression of XIAP and Survivin antiapoptotic genes. Conversely, FOXM1 knockdown results in XIAP and Survivin downregulation as well as decreased binding of FOXM1 to the promoter regions of XIAP and Survivin. Consistently, FOXM1, XIAP, and Survivin expression levels were higher in taxane and anthracycline-resistant cell lines when compared to their sensitive counterparts and could not be downregulated in response to drug treatment. In agreement with our in vitro findings, we found that FOXM1 expression is significantly associated with Survivin and XIAP expression in samples from patients with IIIa stage breast invasive ductal carcinoma. Importantly, patients co-expressing FOXM1, Survivin, and nuclear XIAP had significantly worst overall survival, further confirming the physiological relevance of the regulation of Survivin and XIAP by FOXM1. Together, these findings suggest that the overexpression of FOXM1, XIAP, and Survivin contributes to the development of drug-resistance and is associated with poor clinical outcome in breast cancer patients.
authors.affiliation: Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Praça da Cruz Vermelha, 23/6° andar, Centro, 20230-130 Rio de Janeiro, Brazil; Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Du Cane Road, London W12 0NN, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Nestal de Moraes
authors.affiliation: Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Praça da Cruz Vermelha, 23/6° andar, Centro, 20230-130 Rio de Janeiro, Brazil.
authors.forename: Deborah
authors.initials: D
authors.lastname: Delbue
authors.affiliation: Programa de Biologia Celular, INCA, Rua André Cavalcanti, 37/5° andar, Centro, 20231-050 Rio de Janeiro, Brazil.
authors.forename: Karina L
authors.initials: KL
authors.lastname: Silva
authors.affiliation: Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Praça da Cruz Vermelha, 23/6° andar, Centro, 20230-130 Rio de Janeiro, Brazil.
authors.forename: Marcela Cristina
authors.initials: MC
authors.lastname: Robaina
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Du Cane Road, London W12 0NN, UK.
authors.forename: Pasarat
authors.initials: P
authors.lastname: Khongkow
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Du Cane Road, London W12 0NN, UK.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Gomes
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Du Cane Road, London W12 0NN, UK.
authors.forename: Stefania
authors.initials: S
authors.lastname: Zona
authors.affiliation: Núcleo de Pesquisa Clínica, Hospital de Câncer III, INCA, Rua Visconde de Santa Isabel, 274, Vila Isabel, 20560-120 Rio de Janeiro, Brazil.
authors.forename: Susanne
authors.initials: S
authors.lastname: Crocamo
authors.affiliation: Departamento de Biofísica e Biometria, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro, 87 fundos, 4° andar, Vila Isabel, 20551-030 Rio de Janeiro, Brazil.
authors.forename: André Luiz
authors.initials: AL
authors.lastname: Mencalha
authors.affiliation: Divisão de Anatomia Patológica, INCA, Rua Cordeiro da Graça, 156, Santo Cristo, 20220-400 Rio de Janeiro, Brazil.
authors.forename: Lídia M
authors.initials: LM
authors.lastname: Magalhães
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Du Cane Road, London W12 0NN, UK.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Praça da Cruz Vermelha, 23/6° andar, Centro, 20230-130 Rio de Janeiro, Brazil. Electronic address: rcmaia@inca.gov.br.
authors.forename: Raquel C
authors.initials: RC
authors.lastname: Maia
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D002470:Cell Survival; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000077022:Survivin; D043823:Taxoids / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C107489:BIRC5 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D043823:Taxoids; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077143:Docetaxel; D004317:Doxorubicin
keywords: Breast cancer; Drug resistance; FOXM1; Survivin; XIAP