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.