Estrogen receptor-alpha (ERalpha) and transforming growth factor-beta (TGF-beta) signaling pathways are essential regulators during mammary gland development and tumorigenesis. Ski-related novel gene (SnoN) is an oncoprotein and a negative feedback inhibitor of TGF-beta signaling. We have previously reported that low expression of SnoN in ERalpha positive breast carcinomas is associated with favorable prognosis (Zhang et al. Cancer Res. (2003) 63, 5005-5010). Here we have studied the mechanism of a possible cross-talk between ERalpha and SnoN. We find that SnoN interacts with the estrogen-activated form of ERalpha in the nucleus. SnoN contains two highly conserved nuclear receptor binding LxxLL-like motifs and we show that mutations in these motifs reduce the interaction of SnoN with ERalpha. Over-expression of SnoN enhanced the transcriptional activity of ERalpha in estrogen response element (ERE)-reporter assays, augmented the expression of several ERalpha target genes and increased the proliferation of MCF7 breast carcinoma cells in an estrogen-dependent manner. Chromatin immunoprecipitation demonstrated that SnoN interacts with ERalpha at the TTF1 (pS2) gene promoter. Conversely, silencing of SnoN reduced both ERE-reporter activity and the expression of ERalpha target genes in MCF7 and T-47D breast cancer cells. Histone deacetylase inhibition increased the level of SnoN and SnoN-dependent enhancement of ERalpha-dependent transcription and SnoN supported the recruitment of p300 histone acetylase to ERalpha. This study reveals a novel mechanism that interconnects ERalpha and TGF-beta signaling pathways by SnoN. Accordingly, the results indicate that high SnoN level promotes ERalpha signaling and possibly breast cancer progression.