title: BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells.
abstract: Triple-negative breast cancer (TNBC) has poor prognostic outcome compared with other types of breast cancer. The molecular and cellular mechanisms underlying TNBC pathology are not fully understood. Here, we report that the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumours. Exogenous BCL11A overexpression promotes tumour formation, whereas its knockdown in TNBC cell lines suppresses their tumourigenic potential in xenograft models. In the DMBA-induced tumour model, Bcl11a deletion substantially decreases tumour formation, even in p53-null cells and inactivation of Bcl11a in established tumours causes their regression. At the cellular level, Bcl11a deletion causes a reduction in the number of mammary epithelial stem and progenitor cells. Thus, BCL11A has an important role in TNBC and normal mammary epithelial cells. This study highlights the importance of further investigation of BCL11A in TNBC-targeted therapies.
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK [2] Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK [3].
authors.forename: Walid T
authors.initials: WT
authors.lastname: Khaled
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK [2].
authors.forename: Song
authors.initials: S
authors.lastname: Choon Lee
authors.affiliation: Cancer Research UK Cambridge Institute, and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: John
authors.initials: J
authors.lastname: Stingl
authors.affiliation: SAIC-Frederic, National Cancer Institute-Frederick, Frederick, Maryland 21701, USA.
authors.forename: Xiongfeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: 1] Cancer Research UK Cambridge Institute, and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK [2] Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK.
authors.forename: H
authors.initials: H
authors.lastname: Raza Ali
authors.affiliation: Cancer Research UK Cambridge Institute, and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
authors.forename: Fazal
authors.initials: F
authors.lastname: Hadi
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Juexuan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Cancer Research UK Cambridge Institute, and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Stratton
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Andy
authors.initials: A
authors.lastname: Futreal
authors.affiliation: The Methodist Hospital Research Institute, 6670 Bertner Street, Houston, Texas 77030, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.affiliation: Molecular Oncology Department, BC Cancer Agency Research Centre, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: The Methodist Hospital Research Institute, 6670 Bertner Street, Houston, Texas 77030, USA.
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Watson
authors.affiliation: 1] Cancer Research UK Cambridge Institute, and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK [2] Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK [3] Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000737:chemistry; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012097:Repressor Proteins; D013234:Stem Cells / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism*
chemical_list: C486563:BCL11A protein, human; C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene