Effects of cisplatin and interference peptides on triple negative breast cancers

[Truncated] Triple negative breast cancers (TNBCs) are very aggressive cancers with poor prognosis and very low survival rates, known to be enriched in cancer stem cells (CSCs). CSCs within breast tumours are associated with cell proliferation and metastasis, and a less differentiated tumour phenotype. Previous studies have shown that tumours enriched in CSCs are sensitive to platinum-based anti-cancer drugs, such as cisplatin. The primary aim of this thesis was to examine the anti-cancer effects of cisplatin in TNBCs as a single drug as well as in combination with two new targeted therapies, the Engrailed-1 (EN1) and SOX2 interfering peptides (iPeps), with each targeting a different transcription factor (TF).
In the third chapter, the potential of cisplatin to induce differentiation was examined in breast cancer cell lines that represent different breast cancer subtypes. BT-549, MDA-MB-231 and MDA-MB-468 TNBC cell lines along with estrogen and progesterone receptor positive MCF-7 cells were tested. Cisplatin treatment of 10 μM and 20 μM reduced cell viability by 36-51% and proliferation capacity by 36-67%. This also resulted in 12-67% down-regulation of stem cell markers (CD49f, SSEA4) and 10-130% up-regulation of differentiation markers (CK18, SMA, β-tubulin), demonstrating a shift in the cellular hierarchy of the tumour towards more differentiated cells. At the mRNA level, CD49f was down-regulated, whilst β-tubulin was up-regulated in the claudin-low cell lines, in accordance with the protein data. However, SSEA4 mRNA expression increased, in contrast to the protein levels of this marker which decreased, suggesting differential regulation of cisplatin at the post-transcriptional level. The reduction in breast cancer cell survival and induction of cellular differentiation upon cisplatin treatment provided evidence on the potential of cisplatin to target specific chemotherapy-resistant cells within a tumour.