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Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers

Sarah Naomi Olsen, Ania Wronski, Zafira Castaño, Benjamin Dake, Clare Malone, Thomas De Raedt, Miriam Enos, Yoko S. DeRose, Wenhui Zhou, Stephanie Guerra, Massimo Loda, Alana Welm, Ann H. Partridge, Sandra S. McAllister, Charlotte Kuperwasser and Karen Cichowski
Sarah Naomi Olsen
1Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
2Harvard Medical School, Boston, Massachusetts.
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Ania Wronski
3Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
4Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts.
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Zafira Castaño
2Harvard Medical School, Boston, Massachusetts.
5Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts.
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Benjamin Dake
3Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
4Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts.
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Clare Malone
1Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
2Harvard Medical School, Boston, Massachusetts.
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Thomas De Raedt
1Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
2Harvard Medical School, Boston, Massachusetts.
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Miriam Enos
1Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
2Harvard Medical School, Boston, Massachusetts.
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Yoko S. DeRose
7Huntsman Cancer Institute, Salt Lake City, Utah.
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Wenhui Zhou
3Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
4Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts.
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Stephanie Guerra
1Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
2Harvard Medical School, Boston, Massachusetts.
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Massimo Loda
6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Alana Welm
7Huntsman Cancer Institute, Salt Lake City, Utah.
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Ann H. Partridge
2Harvard Medical School, Boston, Massachusetts.
8Dana-Farber Cancer Institute, Boston, Massachusetts.
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Sandra S. McAllister
2Harvard Medical School, Boston, Massachusetts.
5Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts.
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Charlotte Kuperwasser
3Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
4Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts.
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Karen Cichowski
1Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
2Harvard Medical School, Boston, Massachusetts.
7Huntsman Cancer Institute, Salt Lake City, Utah.
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  • For correspondence: kcichowski@rics.bwh.harvard.edu
DOI: 10.1158/2159-8290.CD-16-0520 Published February 2017
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Abstract

Luminal breast cancers are typically estrogen receptor–positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo. Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.

Significance: The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating RAS and NF-κB. Cancer Discov; 7(2); 202–17. ©2016 AACR.

See related commentary by Sears and Gray, p. 131.

This article is highlighted in the In This Issue feature, p. 115

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received May 5, 2016.
  • Revision received December 9, 2016.
  • Accepted December 12, 2016.
  • ©2016 American Association for Cancer Research.
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Cancer Discovery: 7 (2)
February 2017
Volume 7, Issue 2
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Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers
Sarah Naomi Olsen, Ania Wronski, Zafira Castaño, Benjamin Dake, Clare Malone, Thomas De Raedt, Miriam Enos, Yoko S. DeRose, Wenhui Zhou, Stephanie Guerra, Massimo Loda, Alana Welm, Ann H. Partridge, Sandra S. McAllister, Charlotte Kuperwasser and Karen Cichowski
Cancer Discov February 1 2017 (7) (2) 202-217; DOI: 10.1158/2159-8290.CD-16-0520

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Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers
Sarah Naomi Olsen, Ania Wronski, Zafira Castaño, Benjamin Dake, Clare Malone, Thomas De Raedt, Miriam Enos, Yoko S. DeRose, Wenhui Zhou, Stephanie Guerra, Massimo Loda, Alana Welm, Ann H. Partridge, Sandra S. McAllister, Charlotte Kuperwasser and Karen Cichowski
Cancer Discov February 1 2017 (7) (2) 202-217; DOI: 10.1158/2159-8290.CD-16-0520
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