Human Ovarian Cancer Stroma Contains Luteinized Theca Cells Harboring Tumor Suppressor Gene GT198 Mutations

Peng, Min; Zhang, Hao; Jaafar, Lahcen; Risinger, John I.; Huang, Shuang; Mivechi, Nahid F.; Ko, Lan

doi:10.1074/jbc.m113.485581

Cited by 15 publications

(38 citation statements)

References 38 publications

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“…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).…”

Section: Introductionmentioning

confidence: 99%

Oncoprotein GT198 is a direct target of taxol

Yang

Gurvich²,

Gupta

et al. 2019

Preprint

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Taxol (paclitaxel) is one of the most successful chemotherapeutic drugs in the treatment of human cancer. It has recently been questioned whether the mechanism of action in mitotic arrest, which is ubiquitously present in all cells, is sufficient to explain the tumor specificity, clinical efficacy, and side effects of taxol. In this report, we have identified a new protein target of taxol as GT198 (gene symbol PSMC3IP, also known as Hop2). GT198 is an oncoprotein and a DNA repair factor involved in human common solid tumors. The GT198 gene carries germline mutations in breast and ovarian cancer families and recurrent somatic mutations in tumor microenvironment. Mutant GT198 was identified in pericyte stem cells on capillary blood vessels inducing tumor angiogenesis. GT198 is a DNA-binding protein dimer, also stimulates DNA repair, regulates meiosis, participates in homologous DNA recombination, and activates nuclear receptormediated gene expression. Here we show that taxol directly binds to the DNA-binding domain of GT198 in vitro. Taxol serves as an allosteric inhibitor to block DNA binding to GT198 with an IC50 of 8.6 nM. Labeled taxol colocalizes with GT198 in interphase nuclei of cultured cells. Decreased GT198 expression desensitizes taxolinduced cell death, and taxol inhibits GT198 nuclear foci formation during DNA repair.Together, these results demonstrate that GT198 is a previously unrecognized direct protein target of taxol. The finding of taxol target as an oncoprotein GT198 in common solid tumors provides a rationale for the clinical efficacy of taxol. We anticipate that GT198 may serve as a clinical predictive marker of taxol efficacy as well as a new drug target for future anti-cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Oncoprotein GT198 is a direct target of taxol

Yang

Gurvich²,

Gupta

et al. 2019

Preprint

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“…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 .…”

Section: Discussionmentioning

confidence: 89%

“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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GT198, located 470 kb downstream of BRCA1, encodes for the nuclear PSMC3-interacting protein, which functions as co-activator of steroid hormone-mediated gene expression, and is involved in RAD51 and DMC1-mediated homologous recombination during DNA repair of double-strand breaks. Recently, germline variants in GT198 have been identified in hereditary breast and ovarian cancer (HBOC) patients, mainly in cases with early-onset. We screened a cohort of 166 BRCA1/2 mutation-negative HBOC patients, of which 56 developed early-onset breast cancer before the age of 36 years, for GT198 variants. We identified 7 novel or rare GT198 variants in 8 out of 166 index patients: c.-115G>A (rs191843707); c.-70T>A (rs752276800); c.-37A>T (rs199620968); c.-24C>G (rs200359709); c.519G>A p.(Trp173*); c.537+51G>C (rs375509656); c.*24G>A. Three out of 7 identified variants (c.-115G>A, c.519G>A and c.*24G>A) with putative pathogenic impact were found in HBOC patients with breast cancer onset at ≤ 36 years. The nonsense mutation c.519G>A p.(Trp173*) was located within the DNA binding domain of GT198 and is predicted to induce nonsense-mediated mRNA decay. Functional analyses of c.-115G>A, and c.*24A>G indicated an influence of these variants on gene expression. This is the second study that gives evidence for an association between pathogenic GT198 germline variants and early-onset breast cancer in HBOC.

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“…6 These mutant stromal cells are often found in endometrioid, mucinous, serous, clear cell and granulosa cell tumors, and as well as, endometrial and metastatic gastrointestinal adenocarcinoma. 3,7 A few isolated cases of stromal luteinization has been reported in primary B cell lymphoma of the ovary, 8 ovarian carcinoid, 9 ovarian teratomas, 10 ovarian hemangiomas 11 and Brenner tumors. 6 However, the significance of these luteinized stromal cells is largely unknown.…”

Section: -5mentioning

confidence: 99%

Case Report of Unusual Stromal Luteinization in High-Grade Papillary Serous Carcinoma of the Ovary

Samaila¹,

Sung²,

Lawrence³

et al. 2015

Gynecol Obstet Res Open J

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Case ReportPage 82 ABSTRACTStromal luteinization has been reported to be associated with benign and malignant epithelial ovarian tumors, predominantly mucinous and often endometrioid ovarian neoplasm. We report here an unusual case of marked ovarian stromal luteinization in a 67-year old postmenopausal female with a high-grade serous papillary carcinoma of the ovary. Stromal luteinization was so prominent that the tumor mimicked a Sertoli-Leydig cell tumor of the ovary.

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Human Ovarian Cancer Stroma Contains Luteinized Theca Cells Harboring Tumor Suppressor Gene GT198 Mutations

Cited by 15 publications

References 38 publications

Oncoprotein GT198 is a direct target of taxol

Oncoprotein GT198 is a direct target of taxol

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

Case Report of Unusual Stromal Luteinization in High-Grade Papillary Serous Carcinoma of the Ovary

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