title: Increased Expression of Beige/Brown Adipose Markers from Host and Breast Cancer Cells Influence Xenograft Formation in Mice.
abstract: The initiation and progression of breast cancer is a complex process that is influenced by heterogeneous cell populations within the tumor microenvironment. Although adipocytes have been shown to promote breast cancer development, adipocyte characteristics involved in this process remain poorly understood. In this study, we demonstrate enrichment of beige/brown adipose markers, contributed from the host as well as tumor cells, in the xenografts from breast cancer cell lines. In addition to uncoupling protein-1 (UCP1) that is exclusively expressed in beige/brown adipocytes, gene expression for classical brown (MYF5, EVA1, and OPLAH) as well as beige (CD137/TNFRSF9 and TBX1) adipocyte markers was also elevated in the xenografts. Enrichment of beige/brown characteristics in the xenografts was independent of the site of implantation of the breast tumor cells. Early stages of xenografts showed an expansion of a subset of mammary cancer stem cells that expressed PRDM16, a master regulator of brown adipocyte differentiation. Depletion of UCP1(+) or Myf5(+) cells significantly reduced tumor development. There was increased COX2 (MT-CO2) expression, which is known to stimulate formation of beige adipocytes in early xenografts and treatment with a COX2 inhibitor (SC236) reduced tumor growth. In contrast, treatment with factors that induce brown adipocyte differentiation in vitro led to larger tumors in vivo. A panel of xenografts derived from established breast tumor cells as well as patient tumor tissues were generated that expressed key brown adipose tissue-related markers and contained cells that morphologically resembled brown adipocytes.
  
  
  CONCLUSIONS
  This is the first report demonstrating that beige/brown adipocyte characteristics could play an important role in breast tumor development and suggest a potential target for therapeutic drug design.
authors.affiliation: Charles R. Drew University of Medicine and Science, Los Angeles, California. Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California.
authors.forename: Rajan
authors.initials: R
authors.lastname: Singh
authors.affiliation: Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Meher
authors.initials: M
authors.lastname: Parveen
authors.affiliation: Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: John M
authors.initials: JM
authors.lastname: Basgen
authors.affiliation: Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Sayeda
authors.initials: S
authors.lastname: Fazel
authors.affiliation: Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Meron F
authors.initials: MF
authors.lastname: Meshesha
authors.affiliation: Columbia University, New York, New York.
authors.forename: Easter C
authors.initials: EC
authors.lastname: Thames
authors.affiliation: Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Brandis
authors.initials: B
authors.lastname: Moore
authors.affiliation: Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez
authors.affiliation: Jackson State University, Jackson, Mississippi.
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Howard
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.affiliation: Charles R. Drew University of Medicine and Science, Los Angeles, California. Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California. shehlapervin@cdrewu.edu spervin@mednet.ucla.edu.
authors.forename: Shehla
authors.initials: S
authors.lastname: Pervin
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000071256:Uncoupling Protein 1; D015854:Up-Regulation; D000096926:Benzenesulfonamides
chemical_list: D015415:Biomarkers; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D000071256:Uncoupling Protein 1; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse