Endocrine Abstracts

Introduction: In endocrine tumours, such as that of the breast, the protein survivin has emerged as a unique regulator of cell death. We have previously shown that bFGF regulates survivin expression through the MAP kinase cascade. The transcriptional complex myc/max is an oncogene that lies downstream of the MAP kinase pathway suggesting a possible role in survivin's regulation.

Aim: To determine if bFGF can mediate survivin expression by signalling through the myc/max transcriptional network.

Methods: Survivin protein and RNA levels were determined by Western and Northern blot analysis, respectively, in the breast cancer cell line SKBR3. Survivin and c-Myc protein expression were localised and co-localised in human breast tissue by immunohistochemical and immunoflourescence techniques. The promoter region of survivin was assessed using bioinformatic techniques and DNA footprinting. c-Myc was transfected into SKBR3 cells and the effect on survivin protein expression was examined.

Results: Survivin protein up-regulation was seen from 30mins following stimulation with bFGF over 24hrs. Inhibition of de novo protein synthesis with cycloheximide abrogated bFGF-induced up-regulation of survivin protein from 2hrs, but not at the earlier time points. Survivin mRNA up-regulation in the presence of bFGF was observed only at later time points. Bioinformatical assessment of the survivin promoter revealed putative myc/max response elements, which were confirmed by successful binding of breast cancer nuclear extracts to the Myc/Max response element using DNA footprinting. Over-expression of c-myc increased survivin protein expression.

Conclusion: These data indicate a role for myc/max in the transcriptional regulation of survivin in human breast cancer.