PO-107 A potential role for DELTA40P53 in the regulation of breast cancer stem cells

Introduction Breast cancer is a heterogeneous disease that can be classified as a number of distinct molecular subtypes, however heterogeneity also exists between cancer cells. One class of breast cancer cells that have generated some controversy are breast cancer stem cells (BCSCs). This subpopulation of cells are thought to drive tumourigenesis through their abilities of self-renewal, multilineage differentiation, tumour regrowth, and resistance to chemotherapies. The tumour suppressor p53 is essential in the maintenance of genomic stability in somatic cells. More recently, p53 has been recognised in the maintenance, regulation and characterisation of stem cells, including cancer stem cells. The p53 isoforms, such as Δ40p53, are recognised to play an extensive role in the regulation and function of p53. We have shown that Δ40p53 is the most highly expressed isoform in breast cancer, and a high Δ40p53:p53 ratio was associated with worse prognosis. However, its role in regulating breast cancer stem cells is unknown. Material and methods Gene expression arrays were performed on 64 breast cancers and differentially expressed genes were identified. To investigate the expression of Δ40p53 in breast cancer, we have developed a cell line model that stably overexpresses (LeGO-Δ40p53) Δ40p53. LeGO-Δ40p53 cells were treated with different chemotherapy agents, key targets were assessed by qPCR and immunofluorescence, and DNA-damage measured using Annexin-V apoptosis assay. Results and discussions Differentially expressed genes were identified between breast cancer patients with high and low Δ40p53 expression. These genes significantly enriched for pathways in stem cell regulation and markers of migration/invasion. To confirm this in our cell line model, we found that LeGO-Δ40p53 cells showed significant upregulation of pluripotent markers Nanog, Oct4 and Sox2. In addition, following treatment with doxorubicin, LeGO-Δ40p53 cells showed a reduction in select pro-apoptotic genes and decreased apoptosis, suggesting that high Δ40p53 expression in breast cancer can selectively modulate the DNA-damage response pathway. Conclusion This work suggests that Δ40p53 may play a role in the regulation of breast cancer stem cells and this may be essential for modulating the DNA-damage response in these cells. Further studies are needed to assess if high Δ40p53 expression can alter the functionality of breast cancer stem cells.