Abstract: Objective To elucidate the mechanism of antiestrogen resistance of NSP-2 and its signal pathway in breast cancer cells, we compared NSP-2 with the highly related homologs, NSP-1 and NSP-3 about signaling. Methods ICI 182,780 resistance was detected by cell counting with a hemocytometer; western blot was used to detect Phospho-AKT, Phospho-JNK, Phospho-ERK and Phospho-p38. The activation of cyclin D1 promoter and transcriptional activity of TCF/LEF was performed by Luciferase promoter assay. Results We found that among NSP family members, only NSP-2 can active the cyclinD1 promoter and induce anti-estrogen resistance. Any overexpression of the three NSP family members activated similarly phosphor-Akt in MCF-7 cells. None of them activated Phospho-JNK, Phospho-ERK and Phospho-p38. Over-expression of NSP-2 but not NSP-1 or NSP3 led to activation of the TCF/LEF signaling pathway. Conclusion Over-expression of NSP-2 over-expression to activates TCF/LEF-mediated transcription which may account for the similar unique capacity to induce cyclin D1 promoter activation and anti-estrogen resistance.