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Title: FOXO3a and ID1 as targets of chemotherapy in breast cancer
Author: McGovern, Ursula Brigid
ISNI:       0000 0004 2685 1794
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Cancer is one of the leading causes of death and more than 40000 women are diagnosed every year in the UK with breast cancer. Chemotherapy regimens containing the anthracycline epirubicin are often used in the medical management of breast cancer, but the cellular mechanisms of action and the molecular pathways underlying response to treatment are not fully understood. understood. The FOXO family of transcription factors are downstream targets of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and play a role in a variety of processes including cellular differentiation, metabolism, cell-cycle arrest, cell death and protection from stress. This work identifies the transcription factor FOXO3a as a cellular target of epirubicin. Treatment of the MCF7 breast cancer cell line with epirubicin causes G2/M cell cycle arrest and leads to upregulation of FOXO3a at the transcriptional, translational and gene promoter level. FOXO3a accumulates in the nucleus following treatment with epirubicin and silencing of FOXO3a by RNA interference confers protection against the cytotoxic effects of the drug. FOXM1, another member of the Forkhead family, is repressed at the protein, RNA and gene promoter level by epirubicin. This repression is relieved when FOXO3a is silenced or prevented from binding the FOXM1 promoter in gene promoter assays, suggesting FOXO3a regulates the repression of FOXM1. This work also identifies Id1 as a target of epirubicin. Id1 is highly expressed in chemoresistant cell lines and is rapidly downregulated following treatment of MCF7 cells with epirubicin in sensitive cell lines. Overexpression of Id1 confers resistance to epirubicin and knockdown of Id1 increases the sensitivity of MCF7 cells to a number of chemotherapeutic agents. Id1 activity is independent of FOXO3a regulation. Analysis of clinical samples confirms the changes seen in cell lines in FOXO3a, FOXM1 and Id1 following chemotherapy and treatment with the EGFR inhibitor gefitinib. Thus, in the future, FOXO3a, FOXM1 and Id1 could be used as indicators and predictors of response in the treatment of breast cancer.
Supervisor: Coombes, Charles Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral