title: The co-factor of LIM domains (CLIM/LDB/NLI) maintains basal mammary epithelial stem cells and promotes breast tumorigenesis.
abstract: Mammary gland branching morphogenesis and ductal homeostasis relies on mammary stem cell function for the maintenance of basal and luminal cell compartments. The mechanisms of transcriptional regulation of the basal cell compartment are currently unknown. We explored these mechanisms in the basal cell compartment and identified the Co-factor of LIM domains (CLIM/LDB/NLI) as a transcriptional regulator that maintains these cells. Clims act within the basal cell compartment to promote branching morphogenesis by maintaining the number and proliferative potential of basal mammary epithelial stem cells. Clim2, in a complex with LMO4, supports mammary stem cells by directly targeting the Fgfr2 promoter in basal cells to increase its expression. Strikingly, Clims also coordinate basal-specific transcriptional programs to preserve luminal cell identity. These basal-derived cues inhibit epidermis-like differentiation of the luminal cell compartment and enhance the expression of luminal cell-specific oncogenes ErbB2 and ErbB3. Consistently, basal-expressed Clims promote the initiation and progression of breast cancer in the MMTV-PyMT tumor model, and the Clim-regulated branching morphogenesis gene network is a prognostic indicator of poor breast cancer outcome in humans.
authors: Department of Biological Chemistry, University of California, Irvine, Irvine, California, United States of America; Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America.
authors: Michael L
authors: ML
authors: Salmans
authors: State Key Laboratories for AgroBiotechnology, College of Biological Sciences, China Agricultural University, Beijing, PR China.
authors: Zhengquan
authors: Z
authors: Yu
authors: Department of Biological Chemistry, University of California, Irvine, Irvine, California, United States of America.
authors: Kazuhide
authors: K
authors: Watanabe
authors: Department of Biological Chemistry, University of California, Irvine, Irvine, California, United States of America.
authors: Eric
authors: E
authors: Cam
authors: Department of Biological Chemistry, University of California, Irvine, Irvine, California, United States of America.
authors: Peng
authors: P
authors: Sun
authors: Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America; Department of Computer Science, University of California, Irvine, Irvine, California, United States of America.
authors: Padhraic
authors: P
authors: Smyth
authors: Department of Biological Chemistry, University of California, Irvine, Irvine, California, United States of America.
authors: Xing
authors: X
authors: Dai
authors: Department of Biological Chemistry, University of California, Irvine, Irvine, California, United States of America; Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, California, United States of America; Department of Medicine, University of California, Irvine, Irvine, California, United States of America.
authors: Bogi
authors: B
authors: Andersen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D018295:Neoplasms, Basal Cell / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D014157:Transcription Factors; C486312:LDB1 protein, human; C114905:LMO4 protein, human; C508053:ERBB2 protein, human; C496353:FGFR2 protein, human