TUMORIGENESIS AND NEOPLASTIC PROGRESSION GT 198 Expression De fi nes Mutant Tumor Stroma in Human Breast Cancer

opyright a 2016 American Society for Inve ttp://dx.doi.org/10.1016/j.ajpath.2016.01.006 Human breast cancer precursor cells remain to be elucidated. Using breast cancer gene product GT198 (PSMC3IP; alias TBPIP or Hop2) as a uniquemarker, we revealed the cellular identities of GT198mutant cells in humanbreast tumor stroma. GT198 is a steroid hormone receptor coactivator and a crucial factor in DNA repair. Germlinemutations in GT198 are present in breast and ovarian cancer families. Somaticmutations inGT198 are present in ovarian tumor stromal cells. Herein, we show that human breast tumor stromal cells carry GT198 somaticmutations and express cytoplasmic GT198 protein. GT198þ stromal cells share vascular smoothmuscle cell origin, including myoepithelial cells, adipocytes, capillary pericytes, and stromal fibroblasts. Frequent GT198 mutations are associated with GT198þ tumor stroma but not with GT198 tumor cells. GT198þ 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 formingbreast tumormicroenvironment. GT198expression is, therefore, a specificmarker of mutant breast tumor stroma and has the potential to facilitate diagnosis and targeted treatment of human breast cancer. (Am J Pathol 2016, 186: 1340e1350; http://dx.doi.org/10.1016/j.ajpath.2016.01.006)