Abstract
IntroductionNormal function of the p53 network is lost in most cancers, often through p53 mutation. The clinical impact of p53 mutations in breast cancer remains uncertain, especially where p53 isoforms may modify the effects of these p53 mutations.MethodsExpression of p53β and p53γ isoforms, the isoforms identified in normal breast tissue, was detected by reverse transcription polymerase chain reaction from a cohort of 127 primary breast tumours. Expression of p53β and p53γ isoforms was analysed in relation to clinical markers and clinical outcomes (5 years) by binary logistic regression, Cox proportional hazards regression and Kaplan-Meier survival analyses.Resultsp53β and p53γ were not randomly expressed in breast cancer. p53β was associated with tumour oestrogen receptor (ER) expression, and p53γ was associated with mutation of the p53 gene. The patient group with the mutant p53 breast tumour-expressing p53γ isoform had low cancer recurrence and an overall survival as good as that of patients with wild-type p53 breast cancer. Conversely, patients expressing only mutant p53, without p53γ isoform expression, had a particularly poor prognosis.ConclusionsThe determination of p53γ expression may allow the identification, independently of the ER status, of two subpopulations of mutant p53 breast cancer patients, one expressing p53γ with a prognosis as good as the wild-type p53 breast cancer patients and a second one not expressing p53γ with a particularly poor prognosis. The p53γ isoform may provide an explanation of the hitherto inconsistent relationship between p53 mutation, treatment response and outcome in breast cancer.
Highlights
Normal function of the p53 network is lost in most cancers, often through p53 mutation
Expression of the p53b and p53g isoforms is examined in relation to clinical and pathological markers, p53 mutation and disease outcome in a cohort of 127 randomly selected primary breast tumours
We formed a binary variable (p53m&p53g+ p53b-) that was positive when p53g was expressed in the absence of p53b expression and the p53 gene was mutated (Table 3, row l). These analyses revealed that p53 mutation in patients expressing p53b but not p53g retained the association with death and cancer recurrence (Table 3, compare row c, row i and row k), while p53 mutation in patients without p53b but with p53g was not associated with death and cancer recurrence (Table 3, row c, row j and row l)
Summary
Normal function of the p53 network is lost in most cancers, often through p53 mutation. The p53 pathway is ubiquitously abnormal in human cancers, either through mutation of the p53 gene or via modification of p53 function by interaction with oncogenic cellular or viral proteins [1,2]. Somatic p53 gene mutations, found in about 25% of breast cancers, are associated with poor prognosis [3,4]. We have previously reported that p53 isoforms such as p53b can interact with p53 and modulate p53 tumour suppressor activity [13,19,20]. Taken together, these findings suggest that the p53 isoforms may play a role in human cancers
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