Few genes have been more extensively studied in cancer biology than TP53, the gene coding for the p53 protein. p53 is involved in multiple cellular processes, including growth arrest, senescence, apoptosis and DNA repair; recent evidence has also added necrosis to the list [1]. Its role as a tumour suppressor is well confirmed and patients harbouring germline TP53 mutations suffer a high risk of early cancers. Regarding somatic events, TP53 is the single gene most frequently mutated in malignant conditions, with an incidence rate of 25 to 30% in breast cancers. TP53 mutations have been associated with poor prognosis and, more controversially, with chemosensitivity.

A recent paper by Jackson and colleagues [2] adds interesting information on this topic. In an elegant study using a MMTV-WNT1 mouse mammary tumour model, they generated p53R172H (corresponding to the deleterious human codon 175 mutation), p53-/- and p21-/- mice. As expected, mice carrying homozygous p53 mutations/deletions had shorter tumour latency compared to wild-type mice. Treating animals with established tumours with intraperitoneal doxorubicin (4 mg/kg body weight), they found TP53 mutated tumours to undergo mitotic catastrophe with subsequent cellular death and tumour shrinkage. In contrast, wtTP53 tumours responded to doxorubicin treatment by senescence, lack of tumour shrinkage, and more rapid re-growth. Interestingly, p21-/- tumours revealed an intermediate response; some, but not all, responding by growth arrest. So, what may be the relevance of these findings to human cancers and clinical research?

Clinical data on the predictive role of TP53 mutations for drug resistance versus sensitivity are limited, and we should be aware of their limitations. p53 immunostaining is a poor surrogate marker for TP53 mutation status since 25 to 30% of all TP53 mutations in breast cancer (nonsense mutations associated with drug resistance in particular) do not reveal elevated immunostaining [3]. Taking patients treated with either an anthracycline monotherapy, anthracycline with cyclophosphamide at regular doses or mitomycin regimen, four studies have revealed inferior responses in TP53-mutated tumours [3–6]. Two studies [4, 7] found no effect of TP53 mutation status on response to taxanes. In contrast, de Thé and colleagues [8] reported TP53 mutations to be associated with increased chance of having a complete response. Importantly, in their studies they applied a regimen providing epirubicin (75 mg/m2) and a high dose of cyclophosphamide (1,200 mg/m2) at 2-weekly intervals. Including two additional series of patients treated with either epirubicin monotherapy or a FEC (5-fluorouracil, epirubicin and cyclophosphamide) regimen at regular doses, they confirmed the predictive value of TP53 mutations to pathological complete response was related to dose-dense administration of cyclophosphamide [8]. While conflicting results from human studies may be related to drug regimens applied, it is noteworthy that Jackson and colleagues [2] applied doxorubicin monotherapy at a dose commonly used for such experiments in mice.

In addition to the findings in TP53 itself [3–6], indirect evidence also supports the hypothesis that lack of p53 function may cause drug resistance. Recent studies by our group have linked CHEK2 mutations as well as low ATM-expression (the two most important p53 activators in response to DNA damage [9]) to anthracycline resistance in primary breast cancers harbouring wtTP53 [6, 10].

Importantly, senescence, and probably apoptosis as well, does not occur through activation of just a single gene pathway. Thus, Schmitt and colleagues [11] confirmed senescence activated by the concerted action of the p16/retinoblastoma and p53 pathways to cause tumour regression in response to cyclophosphamide treatment in a mouse lymphoma model. Similar mechanisms may be operating in human tumours; we detected inactivating mutations in the retinoblastoma gene to be associated with resistance toward low-dose anthracycline or mitomycin therapy in primary breast cancers [12].

Our knowledge about the complexity of p53 function is growing [13], and the recent study by Jackson and colleagues [2], together with some other recent remarkable studies [14, 15], indicates that the mechanism of tumour suppression and response to acute DNA damage may be, at least partly, different. Jackson and colleagues' study clearly underlines the need for more sophisticated studies to elucidate the potential role of TP53 status to drug sensitivity in human cancers, bearing in mind potential differences between mice and humans. Further, apart from TP53 mutation status, we need to examine interacting factors; while Jackson and colleagues point to the importance of concomitant TP53 loss of heterozygosity, available human data (although limited) have not defined this as a discriminator [3]. Other factors include p53 splice variants. While p53γ co-expression has been shown to neutralize the poor prognostic impact of TP53 mutations [16], its effect on chemosensitivity, however, remains to be explored. In addition, we need to assess mutations affecting genes acting up/downstream of p53 as well as genes involved in redundant pathways. Most importantly, whenever possible we should collect tissue samples post-chemotherapy to address whether the findings by Jackson and colleagues in their mouse model could be reproduced in humans and correlate potential findings to TP53 status, anti-tumour response and long-term survival.