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.

Oncoprotein GT198 is a direct target of taxol

“…The GT198 mutant cells include pericyte stem cells and the decedent vascular smooth muscle cell lineage. These include myoepithelial cells and adipocytes in breast cancer (21), hormone-producing luteinized theca cells in ovarian cancer (22), myofibroblasts in prostate and bladder cancers (23), pericytes in skin and brain tumors as well as in multiple common solid tumors (24).…”

GT198 (PSMC3IP) germline variants in early-onset breast cancer patients from hereditary breast and ovarian cancer families

“…Interestingly, rare variants within the GT198 5′-UTR and 3′-UTR were frequently found in breast, ovarian and fallopian tube cancers [18,24,28,29]. Six out of 166 cancer patients of our cohort were heterozygous for rare or novel nucleotide substitutions located in the 5´-UTR or 3′-UTR of GT198 .…”

“…For the variants c.-115G>A, and c.*24G>A, no tumor material was available (Table 1). As somatic variants are frequently observed in breast and ovarian cancers [28,29], we sequenced GT198 in the available tumor samples (Table 1, Supplementary Table 2). No additional second hits were detected.…”

“…Three variants (c.-115G>A, c.519G>A and c*24G>A) found in familial breast cancer patients with early-onset at ≤ 36 years seem to have an impact on GT198 function and may contribute to breast cancer predisposition. GT198 participation in steroid hormone receptor-mediated gene expression, its function in DNA recombination, and its ability to stimulate RAD51 mediated DNA strand exchange [18,23,29], makes its implication in oncogenesis conceivable. Further, comprehensive mutation screenings in multi-national case and control collectives are required to evaluate the role of GT198 in breast and ovarian cancer predisposition.…”

“…Subsequently, potential pathogenic germline variants in GT198 were identified at a low frequency in patients with HBOC, mostly with early cancer onset and in one patient with apparently sporadic early-onset breast cancer [18]. Deleterious somatic variants, which often cluster in the 5´-UTR and at the exon 4/intron 4 border of GT198, are abundantly detectable in breast and ovarian cancers and in fallopian tube tumors [18,24,28,29]. In order to evaluate the role of GT198 in HBOC, we screened 166 BRCA1/2 mutation-negative patients, who fulfilled the diagnostic criteria of the German Consortium of Familial Breast and Ovarian Cancer (criteria details see Supplementary Table 1).…”