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Cross-talk between Notch and the Estrogen Receptor in Breast Cancer Suggests Novel Therapeutic Approaches

¹ Breast Cancer Program and ² Skin Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago; ³ Department of Pharmacology, Loyola University Chicago, Maywood, Illinois; ⁴ Department of Pathology, Rush University; ⁵ Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois; ⁶ Department of Pathology, University of Wisconsin, Madison, Wisconsin; and ⁷ Karolinska Institute, Stockholm, Sweden

Requests for reprints: Lucio Miele, Breast Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153. Phone: 708-327-3298; Fax: 708-327-2245; E-mail: lmiele{at}lumc.edu.

Key Words: Notch • breast cancer • estrogen • endocrine therapy • combination therapy

High expression of Notch-1 and Jagged-1 mRNA correlates with poor prognosis in breast cancer. Elucidating the cross-talk between Notch and other major breast cancer pathways is necessary to determine which patients may benefit from Notch inhibitors, which agents should be combined with them, and which biomarkers indicate Notch activity in vivo. We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. Ductal and lobular carcinomas commonly expressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activity did not correlate with Notch receptor levels and was highest in estrogen receptor –negative (ER^–), Her2/Neu nonoverexpressing cells. In ER⁺ cells, estradiol inhibited Notch activity and Notch-1^IC nuclear levels and affected Notch-1 cellular distribution. Tamoxifen and raloxifene blocked this effect, reactivating Notch. Notch-1 induced Notch-4. Notch-4 expression in clinical specimens correlated with proliferation (Ki67). In MDA-MB231 (ER^–) cells, Notch-1 knockdown or -secretase inhibition decreased cyclins A and B1, causing G₂ arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ER⁺) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, -secretase inhibitor treatment arrested the growth of MDA-MB231 tumors and, in combination with tamoxifen, caused regression of T47D:A18 tumors. Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ER⁺ breast cancers and that Notch signaling is a potential therapeutic target in ER^– breast cancers. [Cancer Res 2008;68(13):5226–35]

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				Correction: Estrogen Modulates Notch Activity Cancer Res., September 1, 2008; 68(17): 7246 - 7246. [Full Text] [PDF]