1. ¹Breast Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA
2. ²University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
3. ³Department of Preventive Medicine and Bioinformatics Core, Loyola University Chicago, Maywood, IL, USA
4. ⁴Department of Biochemistry, Boston University, Boston, MA, USA
5. ⁵Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA, USA

Correspondence: L Miele, Ergon Professor of Medicine and Pharmacology, Director, University of Mississippi Cancer Institute, University of Mississippi Medical Center, 2500 N. State Street, Guyton 2 Building, Suite G751-05, Jackson, MS 39216, USA. E-mail: lmiele@ci.umsmed.edu

Received 19 April 2009; Revised 26 August 2009; Accepted 2 September 2009; Published online 19 October 2009.

Abstract

Approximately 80% of breast cancers express the estrogen receptor- (ER) and are treated with anti-estrogens. Resistance to these agents is a major cause of mortality. We have shown that estrogen inhibits Notch, whereas anti-estrogens or estrogen withdrawal activate Notch signaling. Combined inhibition of Notch and estrogen signaling has synergistic effects in ER-positive breast cancer models. However, the mechanisms whereby Notch-1 promotes the growth of ER-positive breast cancer cells are unknown. Here, we demonstrate that Notch-1 increases the transcription of ER-responsive genes in the presence or absence of estrogen via a novel chromatin crosstalk mechanism. Our data support a model in which Notch-1 can activate the transcription of ER-target genes via IKK-dependent cooperative chromatin recruitment of Notch–CSL–MAML1 transcriptional complexes (NTC) and ER, which promotes the recruitment of p300. 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/ER chromatin crosstalk mediates Notch signaling effects in ER-positive breast cancer cells and contributes to regulate the transcriptional functions of ER itself.