Anti-Notch plus endocrine therapy in ER⁺ breast cancer inhibits cancer stem cells by increasing DAXX

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Abstract

Resistance to endocrine therapy (ET) in ER+ breast cancer is mediated by Notch signaling, but the clinical application of anti-Notch therapy has been limited by the lack of predictive biomarkers. To identify Notch-regulated biomarkers, we conducted a pre-surgical window study evaluating ET combined with the γ-secretase inhibitor (GSI) MK-0752. RNA expressions in tumors were measured using an Affymetrix array and by real-time PCR. ET plus GSI showed more genes were decreased than ET alone. Specifically, DAXX, NOXA, and LFNG RNAs were increased, while fifteen additional transcripts were decreased. Mechanistically, GSI reduced Notch1 occupancy at CSL-binding elements within HES1, HEY2, HEYL, CCND1, MKI67, and DAXX genes, and inhibited cancer stem cells (CSCs) by 90% to 100%. This anti-CSC effect required DAXX, while GSI treatment or Notch1/4 knockdown increased DAXX expression, suggesting transcriptional repression by Notch. Using mouse tumor xenograft studies, ET plus MK-0752 resulted in complete regression of MCF-7 tumors, with DAXX-high tumors showing greater treatment sensitivity. Clinically, high DAXX expression was associated with improved recurrence-free and overall survival. This study found that anti-Notch plus ET in ER+ breast cancer inhibits cancer stem cells by increasing DAXX, a promising predictive biomarker. These findings support clinical evaluation of therapies that increase DAXX expression.

Authors

Kathy S. Albain, Debra Wyatt, Andrei Zlobin, Susan G. Hilsenbeck, Cheryl M. Czerlanis, Daniel S. Peiffer, Kyle R. Convington, Constantine Godellas, Shelly S. Lo, Patricia A. Robinson, Kathy Czaplicki, Barbara Busby, Davide Bova, Ping Tang, Patrick J. Stiff, Suzanne A.W. Fuqua, Lucio Miele, Clodia Osipo