Breast cancer is the world’s most prevalent cancer. Although several drugs
and chemotherapeutic strategies have been developed to tackle breast
cancer, to date most patients eventually acquire resistance to these anticancer
therapies. Therefore, identifying ways to increase the efficiency of
currently used chemotherapeutic drugs and the development of new drugs for
breast cancer treatment is essential. One way to achieve this goal is by
identifying cellular targets which play a pivotal role in tumourigenesis and
tumour progression.
Paclitaxel belongs to a class of naturally occurring anti microtubule agents
used for the treatment of malignancies such as breast cancer. Previous work
has shown that FoxO3a, a transcription factor downstream of the
phosphotidylinsitol-3-kinase/Akt signalling pathway, mediates apoptosis and
cell cycle arrest in breast cancer cells in response to paclitaxel treatment.
In order to elucidate the significance of FoxO expression and activation in
response to paclitaxel treatment and oxidative stress (which is caused by
paclitaxel treatment), I investigated the regulation of FoxO in endometrial and
breast cancer cells. Both paclitaxel and oxidative stress were found to upregulate
FoxO expression at the protein, mRNA and gene-promoter levels.
Moreover, treatment with paclitaxel and hydrogen peroxide were shown to
increase FoxO3a protein stability. Paclitaxel treatment resulted in JNK
mediated nuclear accumulation of FoxO3a with a corresponding reduction in
Akt activity. JNK was also shown to induce FoxO3a gene-promoter activity
and to phosphorylate FoxO3a at two sites. These phosphorylation events
may be important in the regulation of FoxO3a stability and activity.
I also investigated the function of FoxO3a, by studying the role of BTG1, a
downstream target of FoxO3a. I found that BTG1 expression was induced at
the gene-promoter level by FoxO3a in MCF-7 cells. The use of a BTG1
inducible MCF-7 cell line revealed that over-expression of BTG1 results in
changes in the expression levels of cell cycle regulators, reduction in cell
growth and accumulation of cells in the G2/M phase of the cell cycle. Taken together, these results show that FoxO expression and activity are upregulated
following paclitaxel treatment and demonstrate that the
PI3K/Akt/FoxO and JNK signalling pathways cross-talk at least at two levels.
Furthermore, these results indicate that FoxO expression levels may serve
as bio-marker for determining the effectiveness of paclitaxel treatment of
breast cancer patients and that FoxOs may serve as a potential target for
anti-cancer chemotherapeutic intervention.