These data again raise the possibility that tumours of this phenotype, expressing elevated PLK1 and harbouring em TP53 /em mutation, may benefit from the use of novel PLK1 inhibitors [7]. The finding that PLK1 expression is associated almost exclusively with tumour grade Stearoylcarnitine (grade 3) could suggest that PLK1 is a passive feature of grade 3 tumours as opposed to a change that may drive tumour development. survival. Results Staining of PLK1 was observed in 11% of Stearoylcarnitine main breast tumours and was significantly associated with the presence of em TP53 /em mutation ( em P /em = 0.0063). Moreover, patients with both PLK1 expression and em TP53 /em mutation showed a significantly worse survival than those with either PLK1 expression or em TP53 /em mutation alone. There was also a close association of elevated PLK1 with triple unfavorable tumours, considered to be poor prognosis breast cancers that generally harbour em TP53 /em mutation. Further association was observed between elevated PLK1 levels and the major p53 unfavorable regulator, MDM2. Conclusions The significant association between elevated PLK1 and em TP53 /em mutation in women with breast malignancy is usually consistent with escape from repression of em PLK1 /em expression by mutant p53. Tumours expressing elevated PLK1, but lacking functional p53, may be potential targets for novel anti-PLK1-targeted drugs. Introduction Breast cancer remains the most common cancer in women in the western world. The genetic and molecular changes underlying the disease are complex. However, understanding the nature of these changes, and their potential for therapeutic exploitation, presents enormous opportunities for individualised approaches to treatment. To explore these possibilities, there is a need to determine whether mechanistic events established in cultured cell systems, which are thought to drive malignancy initiation and/or progression, do indeed underlie the development of the disease in the patients. The screening of clinical material, with focus on the presence or absence of important cancer-associated proteins, should help provide such supporting evidence and identify relevant new candidate markers and therapeutic targets. The p53 tumour suppressor is usually a short-lived Stearoylcarnitine transcription factor that plays a critical role in eliminating tumour cells by coordinating changes in gene expression, leading to cell cycle arrest, senescence or apoptosis [1-3]. p53 regulates the expression of many genes and, accordingly, loss of p53 function during tumour development can have wide-ranging effects for the pathology of the tumour cells [2,4]. Most p53 target genes are actually repressed, as opposed to transactivated, by p53 [1], with the outcome that loss of p53 function may lead to dysregulated or even unrestricted levels of oncogenic proteins. Effective transrepression is usually, therefore, fundamental to p53-mediated tumour suppression, and potentially to clinical end result. Indeed, mutation of the gene encoding p53 ( em TP53 /em ) is usually associated with worse survival in breast malignancy (for example, observe [5]). The protein kinase PLK1 plays a pivotal role in the maturation of centrosomes, access into M phase, spindle formation and cytokinesis [6-8]. Ectopic expression of PLK1 in cultured cells is usually oncogenic [9] and, consistent with this observation, elevated PLK1 levels occur in various human tumour types [10-20], including breast Mouse Monoclonal to Rabbit IgG cancers where it is associated with aggressive characteristics, such as vascular invasion, markers of proliferative activity and lack of detectable estrogen receptor [17,21]. PLK1 is usually down-regulated by p53 as part of the G2/M cell cycle checkpoint [22-29] and we recently established that this occurs mainly through p53-dependent repression of em PLK1 /em expression [30]. Consistent with this observation, we as well as others have also shown that p53-null cells are unable to down-regulate PLK1 levels in response to clinically-relevant genotoxic drugs [26,30]. These data suggest the possibility that tumours lacking functional p53 are likely to have dysregulated PLK1 levels and that these, in turn, may contribute towards development of malignancy. Recent evidence has also suggested that this viability of stressed cells that lack p53 may become dependent upon PLK1 [26]. Given that PLK1 is usually widely considered to be a potential therapeutic target, and that several PLK1 inhibitors are currently undergoing clinical trials [7], targeting of cancers lacking p53 with inhibitors of PLK1 could provide an Stearoylcarnitine effective tailored therapeutic strategy. However, the relationship between PLK1 levels and the status of the p53 pathway in tumours needs to be established. In the present study, we confirm that a proportion.