Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches

Paola Rizzo, Haixi Miao, Gwendolyn D'Souza, Clodia Osipo, Jieun Yun, Huiping Zhao, Joaquina Mascarenhas, Debra Wyatt, Giovanni Antico, Lu Hao, Katharine Yao, Prabha Rajan, Chindo Hicks, Kalliopi Siziopikou, Suzanne Selvaggi, Amina Bashir, Deepali Bhandari, Adriano Marchese, Urban Lendahl, Jian Zhong QinDebra A. Tonetti, Kathy Albain, Brian J. Nickoloff, Lucio Miele*

*Corresponding author for this work

Research output: Contribution to journalArticle

261 Scopus citations

Abstract

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 necessaryto 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 commonlyex pressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activitydid not correlate with Notch receptor levels and was highest in estrogen receptor α-negative (ERAα-), Her2/Neu nonoverexpressing cells. In ERα+ cells, estradiol inhibited Notch activityand Notch-1IC 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 (ERAα-) cells, Notch-1 knockdown or γ-secretase inhibition decreased cyclins A and B1, causing G2 arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ERα+) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, γ-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 maybe effective in ERα+ breast cancers and that Notch signaling is a potential therapeutic target in ERα- breast cancers.

Original languageEnglish (US)
Pages (from-to)5226-5235
Number of pages10
JournalCancer Research
Volume68
Issue number13
DOIs
StatePublished - Jul 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Rizzo, P., Miao, H., D'Souza, G., Osipo, C., Yun, J., Zhao, H., Mascarenhas, J., Wyatt, D., Antico, G., Hao, L., Yao, K., Rajan, P., Hicks, C., Siziopikou, K., Selvaggi, S., Bashir, A., Bhandari, D., Marchese, A., Lendahl, U., ... Miele, L. (2008). Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Research, 68(13), 5226-5235. https://doi.org/10.1158/0008-5472.CAN-07-5744