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SnoN oncoprotein enhances estrogen receptor-? transcriptional activity.

ABSTRACT: Estrogen receptor-? (ER?) and transforming growth factor-beta (TGF-?) 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-? signaling. We have previously reported that low expression of SnoN in ER? 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 ER? and SnoN. We find that SnoN interacts with the estrogen-activated form of ER? 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 ER?. Over-expression of SnoN enhanced the transcriptional activity of ER? in estrogen response element (ERE)-reporter assays, augmented the expression of several ER? target genes and increased the proliferation of MCF7 breast carcinoma cells in an estrogen-dependent manner. Chromatin immunoprecipitation demonstrated that SnoN interacts with ER? at the TTF1 (pS2) gene promoter. Conversely, silencing of SnoN reduced both ERE-reporter activity and the expression of ER? target genes in MCF7 and T-47D breast cancer cells. Histone deacetylase inhibition increased the level of SnoN and SnoN-dependent enhancement of ER?-dependent transcription and SnoN supported the recruitment of p300 histone acetylase to ER?. This study reveals a novel mechanism that interconnects ER? and TGF-? signaling pathways by SnoN. Accordingly, the results indicate that high SnoN level promotes ER? signaling and possibly breast cancer progression.

SUBMITTER: Band AM

PROVIDER: S-EPMC3612938 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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SnoN oncoprotein enhances estrogen receptor-α transcriptional activity.

Band Arja M AM Laiho Marikki M

Cellular signalling 20111229 4

Estrogen receptor-α (ERα) and transforming growth factor-beta (TGF-β) 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-β signaling. We have previously reported that low expression of SnoN in ERα 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 ...[more]

PMID: 22227247

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Project description:BACKGROUND:CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) are approved for the treatment of ER+ advanced breast cancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. We previously reported a novel therapeutic agent, ERX-11, that binds to the estrogen receptor (ER) and modulates ER-coregulator interactions. Here, we tested if the combination of ERX-11 with agents approved for ER+ BCa would be more potent. METHODS:We tested the effect of combination therapy using BCa cell line models, including those that have acquired resistance to tamoxifen, letrozole, or CDK4/6 inhibitors or have been engineered to express mutant forms of the ER. In vitro activity was tested using Cell Titer-Glo, MTT, and apoptosis assays. Mechanistic studies were conducted using western blot, reporter gene assays, RT-qPCR, and mass spectrometry approaches. Xenograft, patient-derived explants (PDEs), and xenograft-derived explants (XDE) were used for preclinical evaluation and toxicity. RESULTS:ERX-11 inhibited the proliferation of therapy-resistant BCa cells in a dose-dependent manner, including ribociclib resistance. The combination of ERX-11 and CDK4/6 inhibitor was synergistic in decreasing the proliferation of both endocrine therapy-sensitive and endocrine therapy-resistant BCa cells, in vitro, in xenograft models in vivo, xenograft-derived explants ex vivo, and in primary patient-derived explants ex vivo. Importantly, the combination caused xenograft tumor regression in vivo. Unbiased global mass spectrometry studies demonstrated profound decreases in proliferation markers with combination therapy and indicated global proteomic changes in E2F1, ER, and ER coregulators. Mechanistically, the combination of ERX-11 and CDK4/6 inhibitor decreased the interaction between ER and its coregulators, as evidenced by immunoprecipitation followed by mass spectrometry studies. Biochemical studies confirmed that the combination therapy significantly altered the expression of proteins involved in E2F1 and ER signaling, and this is primarily driven by a transcriptional shift, as noted in gene expression studies. CONCLUSIONS:Our results suggest that ERX-11 inhibited the proliferation of BCa cells resistant to both endocrine therapy and CDK4/6 inhibitors in a dose-dependent manner and that the combination of ERX-11 with a CDK4/6 inhibitor may represent a viable therapeutic approach.

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SnoN oncoprotein enhances estrogen receptor-? transcriptional activity.

Publications

SnoN oncoprotein enhances estrogen receptor-α transcriptional activity.

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