Notch-1 activates estrogen receptor alpha-dependent transcription via IKK alpha

Approximately 80% of breast cancers express the estrogen receptor α (ERα). ERα belongs to the nuclear receptor superfamily of transcription factors. ERα can extert its functions through both genomic and non-genomic pathways. ER positive breast cancers are treated with anti-estrogens, such as Aromatase inhibitors or SERMs. Resistance to these agents is a major cause of mortality.;Notch is an evolutionarily conserved local cell signaling mechanism that participates in a variety of cellular processes: cell fate specification, differentiation, proliferation, and apoptosis. Notch activates expression of target genes via CSL factors. Notch paralogs have been shown to be oncogenic in T-ALL and many other solid tumor models, including breast cancer. Notch activity has been suggested to correlate with enhanced cell proliferation, anti-apoptosis, and tumor progression in breast cancer. High expression of Notch-1 and its ligand Jagged-1 is especially correlated with poor prognosis.;We have shown that estrogen inhibits Notch, while anti-estrogens or estrogen withdrawal activates Notch signaling. Combined inhibition of Notch and estrogen signaling has synergistic effects in ERα-positive breast cancer models. However, the mechanisms whereby Notch-1 promotes the survival of ERα-positive breast cancer cell are unknown. Here, we demonstrate that Notch-1 increases the transcription of ERα-responsive genes in the presence or absence of estrogen via a novel chromatin cross-talk mechanism. Our data support a model in which Notch-1 can activate the transcription of ERα target genes via IKKα-dependent cooperative chromatin recruitment of Notch-CSL-MAML1 transcriptional complexes (NTC) and ERα. We have also demonstrated that the canonical co-activators of ERα are not required for this transactivation mechanism. However, IKKα and MAML1 are indespensible in the recruitment of p300 and the subsequent transcriptional activation.;CSL binding elements frequently occur in close proximity to estrogen-responsive elements (EREs) in the human and mouse genomes. Our observations suggest that a hitherto unknown Notch-1/ERα chromatin cross-talk mediates Notch signaling effects in ERα-positive breast cancer. Taken together, our findings confirmed the critical role of Notch in ER positive breast cancer cells deprived of estrogen signaling, and suggested activation of Notch signaling may contribute to the development of resistance to endocrine therapies in breast cancer patients.