Basic fibroblast growth factor (bFGF, FGF-2), a classical transforming factor, mitogen, and survival factor in multiple cell types, and has a paradoxic role in mammary epithelial cell transformation and proliferation. We have also demonstrated that recombinant FGF-2 uncharacteristically promotes cell death in MCF-7 human breast cancer cells. In this study, we investigated the effects of FGF-2 overexpression on survival in the same MCF-7 cells. In eight breast cancer cell lines and two nontransformed mammary epithelial cell lines, we demonstrated that high levels of Bcl-2 are only expressed in cells with undetectable levels of FGF-2 on western blot. In retrovirally transduced MCF-7 cells expressing both cytoplasm- and nucleus-localizing FGF-2 species and ones expressing only cytoplasm-localizing FGF-2 species, Bcl-2 levels were strongly decreased at both the mRNA and protein levels. Immunoprecipitation of Bax demonstrated a decreased association of Bax with Bcl-2 in these cells. Levels of Bax did not correlate with expression of FGF-2 in the 10 cell lines or in MCF-7 cells. The clonogenic potential of MCF-7 cells in tissue culture was decreased by the expression of FGF-2 and was additively suppressed by the chemotherapeutic agents etoposide and 5-fluorouracil in a dose and time dependent manner. MCF-7 cells overexpressing FGF-2 had a greater rate of programmed cell death at baseline and in response to etoposide and 5-fluorouracil in a TUNEL assay by immunofluorescent microphotography and by flow cytometric quantitation. The pro-apoptotic effect of FGF-2 overexpression on the chemosensitivity of these cells was confirmed by quantitative morphologic determination. These data demonstrate that the expression of FGF-2 downregulates Bcl-2 and promotes programmed cell death in MCF-7 human breast cancer cells.