title: Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers.
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.
  
  
  
  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. 131This article is highlighted in the In This Issue feature, p. 115.
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Sarah Naomi
authors.initials: SN
authors.lastname: Olsen
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.|Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Ania
authors.initials: A
authors.lastname: Wronski
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Hematology 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.
authors.forename: Zafira
authors.initials: Z
authors.lastname: Castaño
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.|Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dake
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Clare
authors.initials: C
authors.lastname: Malone
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: De Raedt
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Miriam
authors.initials: M
authors.lastname: Enos
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, Utah.
authors.forename: Yoko S
authors.initials: YS
authors.lastname: DeRose
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.|Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Guerra
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, Utah.
authors.forename: Alana
authors.initials: A
authors.lastname: Welm
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ann H
authors.initials: AH
authors.lastname: Partridge
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Hematology 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.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: McAllister
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.|Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kuperwasser
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. kcichowski@rics.bwh.harvard.edu.|Harvard Medical School, Boston, Massachusetts.|Huntsman Cancer Institute, Salt Lake City, Utah.
authors.forename: Karen
authors.initials: K
authors.lastname: Cichowski
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020690:GTPase-Activating Proteins; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C462952:DAB2IP protein, human; D020690:GTPase-Activating Proteins; D016328:NF-kappa B; C576391:RASAL2 protein, human; D020703:ras GTPase-Activating Proteins; D016283:Proto-Oncogene Proteins p21(ras)