FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance

• Published in: Cellular signalling Vol. 27; no. 12; pp. 2496 - 2505
• Main Authors: Nestal de Moraes, Gabriela, Delbue, Deborah, Silva, Karina L., Robaina, Marcela Cristina, Khongkow, Pasarat, Gomes, Ana R., Zona, Stefania, Crocamo, Susanne, Mencalha, André Luiz, Magalhães, Lídia M., Lam, Eric W.-F., Maia, Raquel C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-12-2015
• Subjects: Antibiotics, Antineoplastic - pharmacology; Base Sequence; Binding Sites; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Cell Survival; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Neoplasm; Female; Forkhead Box Protein M1; Forkhead Transcription Factors - physiology; FOXM1; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Kaplan-Meier Estimate; MCF-7 Cells; Middle Aged; Prognosis; Promoter Regions, Genetic; Protein Binding; Survivin; Taxoids - pharmacology; X-Linked Inhibitor of Apoptosis Protein - genetics; X-Linked Inhibitor of Apoptosis Protein - metabolism; XIAP; PBS; IHC; TMA; XIAP; HR; siRNA; Breast cancer; Survivin; ChIP; MTT; FOXM1; Drug resistance; FOX; FHRE; FISH; IAP
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2015.09.013

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.
•In drug resistant cells, XIAP and Survivin expression is upregulated by FOXM1.•XIAP and Survivin levels are inhibited in FOXM1-depleted breast cancer cells.•FOXM1 knockdown results in decreased binding to XIAP and Survivin gene promoters.•In breast cancer patients, FOXM1 is associated with XIAP and Survivin expression.•Co-expression of FOXM1, Survivin, and nuclear XIAP impacts breast cancer survival.