Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways

We show here that the neurotrophin nerve growth factor (NGF), which has bee n shown to be a mitogen for breast cancer cells, also stimulates cell survi val through a distinct signaling pathway. Breast cancer cell lines (MCF-7, T47-D, BT-20, and MDA-MB-231) were found to express both types of NGF recep tors: p140(trkA) and p75(NTR). The two other tyrosine kinase receptors for neurotrophins, TrkB and TrkC, were not expressed. The mitogenic effect of N GF on breast cancer cells required the tyrosine kinase activity of p140(trk A) as well as the mitogen-activated protein kinase (MAPK) cascade, but was independent of p75(NTR). I, contrast, the anti-apoptotic effect of NGF (stu died using the ceramide analogue C2) required p75(NTR) as well as the activ ation of the transcription factor NF-kB, but neither p140(trkA) nor MAPK wa s necessary. Other neurotrophins (BDNF, NT-3, NT-4/5) also induced cell sur vival, although not proliferation, emphasizing the importance of p75(NTR) i n NGF-mediated survival. Both the pharmacological NF-KB inhibitor SN50, and cell transfection with IkBm, resulted in a diminution of NGF anti-apoptoti c effect. These data show that two distinct signaling pathways are required for NGF activity and confirm the roles played by p75(NTR) and NF-kappaB in the activation of the survival pathway in breast cancer cells.