The relative mRNA expression of p53 isoforms in breast cancer is associated with clinical features and outcome

Abstract

Mutation of p53 is a common feature of cancer. Breast cancer is the most common malignancy that develops in women; however, somatic mutation of p53 is rare, suggesting that p53 becomes inactivated by other mechanisms. p53 is expressed as smaller isoforms, some of which inhibit wild-type p53. There are no studies that have examined the relative expression of all isoforms in this disease. We have analysed the relative messenger RNA expression of the p53 isoforms, Δ40, Δ133, β and γ in a panel of 6 breast cancer cell lines, 148 breast cancers specimens and 31 matched normal adjacent tissues by semi-quantitative real-time reverse transcription-PCR and analysed their relationship to clinical features and outcome. We have identified several important clinical associations, particularly with Δ40p53, which was expressed at levels that were ~50-fold higher than the least expressed isoform p53γ. Δ40p53 was significantly upregulated in tumour tissue when compared with the normal breast and was significantly associated with an aggressive breast cancer subtype-triple negative. Additionally, p53β expression was significantly negatively associated with tumour size and positively associated with disease-free survival, where high levels of p53β were protective, particularly in patients with a mutation in p53, suggesting p53β may counteract the damage inflicted by mutant p53. In conclusion, the relative expression of p53 isoforms is related to clinical features of breast cancer and outcome. These results have implications for the stratification of breast cancer based on p53 function and may provide an alternate explanation for deregulated p53 signalling in breast cancer.

A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology

“…Elevated expression of the D40p53 isoform has been associated with metastatic melanoma and triple-negative breast cancers (7,19). In contrast, elevated levels of TP53b were found to be negatively associated with tumor size and positively associated with disease-free survival of breast cancer patients with TP53 mutations (7). Opposing functions of these two isoforms was further demonstrated in melanoma cell lines where D40p53 was shown to inhibit p53-dependent transcription of downstream target genes, whereas p53b stimulated transactivation (19).…”

“…Elevated expression of the D40p53 isoform has been associated with metastatic melanoma and triple-negative breast cancers (7,19). In contrast, elevated levels of TP53b were found to be negatively associated with tumor size and positively associated with disease-free survival of breast cancer patients with TP53 mutations (7).…”

“…Multiple studies have now shown that p53 isoforms have distinct functions and frequently contribute to diseases including cancer (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Elevated expression of the D40p53 isoform has been associated with metastatic melanoma and triple-negative breast cancers (7,19).…”

Modulation of alternative splicing contributes to cancer development: focusing on p53 isoforms, p53β and p53γ

“…Specifically, breast cancer studies show that their levels are associated with better disease outcome. 15,16 This study (Marcel et al) examined a cohort of 85 primary breast cancer tumors and found positive correlation of SFRS1 with p53a and with lack of detection of p53b. This supports the suggested mechanism underlying p53 splicing of intron 9, and show that it is relevant to human pathological conditions.…”

“…15 Recently, p53b expression was found to be associated with breast cancer disease-free survival and was further found as protective in patients expressing mutant p53. 16 In addition, it was shown that D133p53 is associated with improved prognosis and survival of mutant p53 expressing advanced serous ovarian cancers. 17 Altogether, these examples point p53 isoforms as biomarkers for cancer prognosis and suggest that uncovering the molecular mechanism controlling the expression of the various p53 variants could contribute to the development of personalized medicine.…”