Association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancer

Abstract

Survivin, a member of the inhibitory apoptosis protein family, gives rise, by an alternative splicing, to four variants with different functions. Many experimental studies indicate that p53 can regulate the expression of survivin and some of its splice variants. Although both the expression of survivin splice variants and the p53 gene were frequently altered in human cancers, nothing is known about their interactions in in vivo tumour samples. Here, we report that, in 162 breast carcinomas, p53 mutations are significantly associated with an increased expression of survivin and, in particular, its antiapoptotic splice variants (survivin-DEx3 and survivin-3B). The upregulation of these variant expressions is particularly related to p53 mutations occurring in the residues belonging to the tetramerization domain. The loss of heterozygosity in the p53 gene is also associated with an increased expression of the survivin-DEx3 variant. The expression of the proapoptotic variants (survivin-2B and survivin-2a) is not affected by any of these alterations. Our results provide for the first time in vivo evidence that, in human breast cancer, the survivin expression as well as its splicing depends on the p53 status. The results also suggest that the upregulation of antiapoptotic survivin variant expression by the mutant p53 may increase breast cancer cells survival and resistance to therapy.

The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism

“…This study was done with the approval of the local boards governing research on human subjects. DNA and total RNA were extracted as described previously (Ve´gran et al, 2007). After extraction by TRIzol reagent, protein pellets were kept and used for GATA-1 western blotting on 10 breast carcinomas and their adjacent normal tissues.…”

“…Western blots were performed as described previously (Ve´gran et al, 2007) with following primary antibodies (Abcam, Cambridge, UK): b-actin 1:25 000, GFP 1:50 000, GATA-1 1:5000 or Survivin 1:5000.…”

“…It is strongly expressed in fetal tissues whereas its expression in adult ones is limited to specific tissues including thymus, placenta, spleen, intestinal crypt epithelium and bone marrow (Ambrosini et al, 1997;Altieri and Marchisio, 1999;Li, 2003). The transcript is also sharply differentially expressed in human cancers (Ambrosini et al, 1997;Li, 2003), including breast cancer (Nasu et al, 2002;O'Driscoll et al, 2003;Ryan et al, 2005;Ve´gran et al, 2005Ve´gran et al, , 2007Boidot et al, 2009). Survivin is encoded by a complex gene, and its expression is finely regulated by transcriptional and post-transcriptional mechanisms.…”

Immunoexpression of inhibitors of apoptosis proteins and their antagonist SMAC/DIABLO in colorectal carcinoma: Correlation with apoptotic index, cellular proliferation and prognosis

“…Survivin is overexpressed in a series of transformed cell lines and in lung, intestine, pancreas, prostrate and breast cancer cells and non-Hodgkin lymphoma, and is associated with recurrence risk factors and poor prognosis. It is significantly correlated with p53 protein mutation in breast carcinomas (11)(12)(13)(24)(25)(26).…”

Association between survivin −31G>C promoter polymorphism and cancer risk: a meta-analysis

“…Twelve of these articles did not explore the survivin À31G/C polymorphism and were excluded. [28][29][30][31][32][33][34][35][36][37][38][39] Four of these articles did not explore cancer risk and were excluded. [40][41][42][43] Finally, 13 case-control studies and 1 cohort study 44 that comprised a total of 3485 cancer cases and 3964 controls were included in our meta-analysis, and are presented in Table 1.…”