Our lab group has recently reported that FGF2 induces non apoptotic cell death in mouse Y1 adrenocortical tumor cells, by a process dependent on high levels of c-KRas-GTP onco-protein. Here we show that cell death induced by FGF2 correlates well with both growth in suspension cultures (transformed phenotype) and tumor growth in immuno-deficient Balb/c-Nude mice. Y1 adrenocortical cells and a Y1 sub-line ectopically over-expressing Cyclin D1 onco-protein (Y1-D1 clone G) are both transformed in culture (250-350 large visible colonies/10,000 cells in agarose suspension in 25 days) and highly tumorigenic in Nude mice (tumor up to 550 mm³ in every animal injected with 500,000 cells within 21 days). FGF2 severely inhibits colony growth of both cell lines in solid substrate and suspension cultures, respectively: 92% inhibition for Y1 cells and >95% for the Y1-D1G sub-line. Thus, both cell lines are extremely sensitive to FGF2 toxic effects. In addition, we selected and isolated clonal sub-lines of Y1-D1G resistant to FGF2 in monolayer cultures. 2 FGF2 resistant clones, Y1-D1G-FR 5.3 and Y1-D1G-FR10.4 were analyzed for growth phenotypes. D1G-FR10.4 is partially resistant (50%) to FGF2 in colony development assays in solid substrate; grows poorly in suspension cultures (10-4 colonies/10,000 cells) and displays low tumorigenicity (2 slow growing tumors/5 animals). Furthermore, the clone D1G-FR 5.4 is fully resistant to FGF2 in monolayer cultures, cannot grow in suspension cultures and is not tumorigenic in Nude mice. Interestingly, both D1G-FR1 and –FR2 grow well in suspension cultures (300-350 colonies/10,000 cells) if the medium is supplemented with FGF2. Therefore these selection experiments led to segregation of the 2 main effects of FGF2, namely: the classical growth promoting effect and the novel cell death induction effect. Moreover, altogether these results support the conclusion that FGF2 cell death response is a phenotypic trait strictly correlated with transformation in cultures and tumorigenicity in Nude mice.