LAUSR

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer affecting approximately 20% of women. TNBC cells lack three key receptors: progesterone, oestrogen and Her2, and as a result, TNBC cannot be treated using existing targeted therapies; therefore patients have an extremely poor prognosis. Recently selenium based drugs have been proposed as therapeutics to treat a range of disorders, and here we investigated the potential of these drugs to target TNBC. Representative selenium compounds diphenyl selenide (DPS) and diphenyl diselenide (DPDS) were characterised by their cytotoxicity against the TNBC cell lines: MDA-MB-231, MDA-MB-468 and HS-578T and, to probe selectivity, against the non-TNBC line SK-BR-3, which expresses Her2. DPS showed no anti-cancer action against any breast cancer cells, however, its structural analogue DPDS showed pronounced cytotoxicity in the range 5-20 μM against all TNBC cell lines studied. Interestingly neither drug displayed cytotoxicity towards a non-TNBC cell line, indicating that DPDS may be capable of selectively destroying TNBC cells without damaging the surrounding healthy cells in the cancerous tissue. Mechanistic analysis indicated that DPDS induced apoptosis in TNBC via a caspase-3 dependent mechanism which correlated with p53 upregulation and membrane changes characteristic of apoptosis. In addition, drug-induced morphological changes characteristic of apoptosis, including membrane disruption and cell shrinkage, were observed in all TNBC cell lines using phase contrast microscopy. These findings provide the first evidence that DPDS may be a selective anti-cancer drug towards TNBC, and identify crucial structural features for TNBC activity, paving the way towards a next generation treatment for a cancer with a notoriously low survival rate.