The clinical relevance of p53 isoforms modifying the effects of p53 mutation on survival from breast cancer

Abstract

10505 Background: p53 is a key gene in the development of breast cancer and response to therapy. Nine splice variants of p53 in breast cancer have been identified, with full length p53, p53beta and p53gamma (both 46kD, C terminal truncated proteins) commonly expressed. This study examined the clinical relevance of splice variants in breast cancer. Methods: Tumors from 248 patients with primary breast cancer were examined for mutation with the Roche p53 mutation chip and p53 isoform expression detected by RT-PCR followed by nested PCR; full clinical and pathological data included median follow up of 6.4 years. Results: p53 mutation, identified in 65/248 (26%) cancers, was significantly associated by Chi square test with shorter survival (p=0.001), histological grade 3 (p<0.001) and estrogen receptor (ER) negative cancers (p<0.001), as expected. Expression of p53 beta or p53 gamma mRNA was associated with p53 mutation (p=0.002, Fisher's exact test). Intriguingly, the patient groups with a mutant p53 cancer but expressing p53 gamma or p53 beta or both isoforms had survival curves comparable to patients with cancer containing wild type p53. Similarly, p53 gamma or p53 beta was associated with ER negative cancers (Chi square; p<0.001), but the group of ER negative tumors expressing p53 gamma or p53 beta had improved survival similar to ER positive cancers. Patients with p53 mutant, p53 beta negative and ER negative cancers comprised half of those who died within 3 years of diagnosis. Conclusions: p53 beta or p53 gamma isoform expression in breast cancer is associated with better prognosis and may moderate disease behaviour even in mutant p53 and ER negative cancers. Manipulation of p53 isoforms in breast cancer may thus offer therapeutic potential. No significant financial relationships to disclose.