Prosaposin, a secreted protein, is a well-known pleiotropic growth factor. Although a previous report has indicated that prosaposin is overexpressed in breast cancer cell lines, the role of prosaposin in the development of breast cancer remains to be identified. Here, we first revealed that prosaposin upregulated estrogen receptor alpha expression, nuclear translocation and transcriptional activity by western blot, immunofluorescence assay and dual luciferase reporter gene assay, respectively. Furthermore, we demonstrated prosaposin upregulated estrogen receptor alpha expression through MAPK-signaling pathway using MAPK inhibitor. Proliferation assay and tumor xenograft experiments in nude mice (n = 6 per group) further confirmed prosaposin could promote breast cancer growth significantly in vitro and in vivo. These findings suggested that prosaposin might enhance estrogen receptor alpha-mediated signaling axis and play a role in breast cancer development and progression.