title: KSR1 regulates BRCA1 degradation and inhibits breast cancer growth.
abstract: Kinase suppressor of Ras-1 (KSR1) facilitates signal transduction in Ras-dependent cancers, including pancreatic and lung carcinomas but its role in breast cancer has not been well studied. Here, we demonstrate for the first time it functions as a tumor suppressor in breast cancer in contrast to data in other tumors. Breast cancer patients (n>1000) with high KSR1 showed better disease-free and overall survival, results also supported by Oncomine analyses, microarray data (n=2878) and genomic data from paired tumor and cell-free DNA samples revealing loss of heterozygosity. KSR1 expression is associated with high breast cancer 1, early onset (BRCA1), high BRCA1-associated ring domain 1 (BARD1) and checkpoint kinase 1 (Chk1) levels. Phospho-profiling of major components of the canonical Ras-RAF-mitogen-activated protein kinases pathway showed no significant changes after KSR1 overexpression or silencing. Moreover, KSR1 stably transfected cells formed fewer and smaller size colonies compared to the parental ones, while in vivo mouse model also demonstrated that the growth of xenograft tumors overexpressing KSR1 was inhibited. The tumor suppressive action of KSR1 is BRCA1 dependent shown by 3D-matrigel and soft agar assays. KSR1 stabilizes BRCA1 protein levels by reducing BRCA1 ubiquitination through increasing BARD1 abundance. These data link these proteins in a continuum with clinical relevance and position KSR1 in the major oncoprotein pathways in breast tumorigenesis.
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 1] Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, London, UK [2] Faculty of Medicine, Department of Physiology, University of Malaya, Kuala, Lumpur, Malaysia.
authors.forename: L C
authors.initials: LC
authors.lastname: Lit
authors.affiliation: Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospital NHS Trust, Nottingham, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Grothey
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Lombardo
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Periyasamy
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK.
authors.forename: K
authors.initials: K
authors.lastname: Blighe
authors.affiliation: Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Centre, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Shaw
authors.affiliation: Faculty of Medicine, Department of Physiology, University of Malaya, Kuala, Lumpur, Malaysia.
authors.forename: I O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Centre, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Giamas
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D000071877:Checkpoint Kinase 1; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C097199:KSR-1 protein kinase; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse