Basic fibroblast growth factor (FGF) promotes branching neuritogenesis and survival in rat hippocampal neurons in vitro. Basic FGF is a broad spectrum mitogen which does not normally circulate, but increases in serum from a variety of cancers. In prior work, we described spontaneously-occurring fibroblast growth factor-like autoantibodies in serum from a subset of breast cancer patients with neurological complications. The FGF-like autoantibodies mimicked the potent endothelial cell growth-promoting activity of bFGF yet had remarkably increased stability (activity survived storage at 0-4 degrees C for up to 5 years). In the present study we tested whether FGF-like autoantibodies from breast cancer sera is neurotrophic or neuroprotective. We now report that FGF-like autoantibodies (2-3 microg/mL) from breast cancer sera promoted neuritogenesis in DIV 12 embryonic day 18 rat hippocampal neurons and neurite extension in undifferentiated rat pheochromocytoma PC12 cells. The FGF-like autoantibodies from a breast cancer patient with lupus were unique in protecting rat hippocampal neurons from glutamate-induced cell loss and promoting long-lasting neurite extension and survival in PC-12 cells (up to 25 days in vitro). Breast cancer sera FGF-like autoantibodies induced large sustained increases in inward cationic current associated with depolarization in hippocampal neurons that exceeded the electrophysiological effects of substantial concentrations of basic FGF. These results suggest that differences in potency or other unknown factors contribute to whether subsets of FGF-like autoantibodies from breast cancer sera exhibit long-lasting neurotrophic and neuroprotective effects or an early neurotrophic effect followed by accelerated late neuron death.