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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/jci.insight.172506

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

Kathy S. Albain,1 Debra Wyatt,2 Andrei Zlobin,2 Susan G. Hilsenbeck,3 Cheryl M. Czerlanis,4 Daniel S. Peiffer,5 Kyle R. Convington,3 Constantine Godellas,6 Shelly S. Lo,7 Patricia A. Robinson,8 Kathy Czaplicki,1 Barbara Busby,1 Davide Bova,9 Ping Tang,10 Patrick J. Stiff,1 Suzanne A.W. Fuqua,3 Lucio Miele,11 and Clodia Osipo2

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Albain, K. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Wyatt, D. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Zlobin, A. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Hilsenbeck, S. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Czerlanis, C. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Peiffer, D. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Convington, K. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Godellas, C. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Lo, S. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Robinson, P. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Czaplicki, K. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Busby, B. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Bova, D. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Tang, P. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Stiff, P. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Fuqua, S. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Miele, L. in: PubMed | Google Scholar

1Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, United States of America

2Department of Cancer Biology, Loyola University Chicago, Maywood, United States of America

3Baylor College of Medicine, Houston, United States of America

4University of Wisconsin Health, Madison, United States of America

5Department of Medicine, University of Chicago, Chicago, United States of America

6Department of Surgery, Division of Surgical Oncology, Ascension Medical Group Illinois, Elk Grove Village, United States of America

7RUSH MD Anderson Cancer Center, Rush University Medical Center, Chicago, United States of America

8Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, United States of America

9Department of Radiology, Loyola University Chicago Stritch School of Medicine, Maywood, United States of America

10Division of Surgical Pathology, Cook County Health, Chicago, United States of America

11Department of Microbiology, Genetics and Immunology, Louisiana State University Health Sciences Center and LSU-LCMC Health Cancer Center, New Orleans, United States of America

Find articles by Osipo, C. in: PubMed | Google Scholar

Published September 29, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.172506.
Copyright © 2026, Albain et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 29, 2026 - Version history
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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.

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