title: GT198 Expression Defines Mutant Tumor Stroma in Human Breast Cancer.
abstract: Human breast cancer precursor cells remain to be elucidated. Using breast cancer gene product GT198 (PSMC3IP; alias TBPIP or Hop2) as a unique marker, we revealed the cellular identities of GT198 mutant cells in human breast tumor stroma. GT198 is a steroid hormone receptor coactivator and a crucial factor in DNA repair. Germline mutations in GT198 are present in breast and ovarian cancer families. Somatic mutations in GT198 are present in ovarian tumor stromal cells. Herein, we show that human breast tumor stromal cells carry GT198 somatic mutations and express cytoplasmic GT198 protein. GT198(+) stromal cells share vascular smooth muscle cell origin, including myoepithelial cells, adipocytes, capillary pericytes, and stromal fibroblasts. Frequent GT198 mutations are associated with GT198(+) tumor stroma but not with GT198(-) tumor cells. GT198(+) progenitor cells are mostly capillary pericytes. When tested in cultured cells, mutant GT198 induces vascular endothelial growth factor promoter, and potentially promotes angiogenesis and adipogenesis. Our results suggest that multiple lineages of breast tumor stromal cells are mutated in GT198. These findings imply the presence of mutant progenitors, whereas their descendants, carrying the same GT198 mutations, are collectively responsible for forming breast tumor microenvironment. GT198 expression is, therefore, a specific marker of mutant breast tumor stroma and has the potential to facilitate diagnosis and targeted treatment of human breast cancer.
authors.affiliation: Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Zheqiong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia; Oncology Center, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Kimya
authors.initials: K
authors.lastname: Jones
authors.affiliation: Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Obstetrics Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Nita J
authors.initials: NJ
authors.lastname: Maihle
authors.affiliation: Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Nahid F
authors.initials: NF
authors.lastname: Mivechi
authors.affiliation: Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Pathology, Medical College of Georgia, Augusta University, Augusta, Georgia. Electronic address: LKO@augusta.edu.
authors.forename: Lan
authors.initials: L
authors.lastname: Ko
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D000071960:Breast Carcinoma In Situ / Q000175:diagnosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis / Q000235:genetics*; D055088:Early Detection of Cancer; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005819:Genetic Markers / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; D009687:Nuclear Proteins; C443678:PSMC3IP protein, human; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A