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

Schubert, Stephanie; Ripperger, Tim; Rood, Melanie; Petkidis, Anthony; Hofmann, Winfried; Frye-Boukhriss, Hildegard; Tauscher, Marcel; Auber, Bernd; Hille-Betz, Ursula; Illig, Thomas; Schlegelberger, Brigitte; Steinemann, Doris

doi:10.18632/genesandcancer.132

Cited by 11 publications

(8 citation statements)

References 42 publications

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“…The human GT198 gene ( PSMC3IP ; encodes GT198, also known as Hop2 or TBPIP) is a DNA repair gene and also a breast and ovarian cancer gene located within the BRCA1 locus at chromosome 17q21. Germline mutations in GT198 have been identified in familial breast and ovarian cancer [ 37 , 38 ]. Somatic mutations in GT198 are prevalent in tumor stroma in sporadic breast, ovarian, and fallopian tube cancers [ 39 – 41 ].…”

Section: Introductionmentioning

confidence: 99%

Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis

et al. 2017

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Angiogenesis promotes tumor development. Understanding the crucial factors regulating tumor angiogenesis may reveal new therapeutic targets. Human GT198 (PSMC3IP or Hop2) is an oncoprotein encoded by a DNA repair gene that is overexpressed in tumor stromal vasculature to stimulate the expression of angiogenic factors. Here we show that pericytes expressing GT198 give rise to tumor cells through angiogenesis. GT198+ pericytes and perivascular cells are commonly present in the stromal compartment of various human solid tumors and rodent xenograft tumor models. In human oral cancer, GT198+ pericytes proliferate into GT198+ tumor cells, which migrate into lymph nodes. Increased GT198 expression is associated with increased lymph node metastasis and decreased progression-free survival in oral cancer patients. In rat brain U-251 glioblastoma xenografts, GT198+ pericytes of human tumor origin encase endothelial cells of rat origin to form mosaic angiogenic blood vessels, and differentiate into pericyte-derived tumor cells. The net effect is continued production of glioblastoma tumor cells from malignant pericytes via angiogenesis. In addition, activation of GT198 induces the expression of VEGF and promotes tube formation in cultured U251 cells. Furthermore, vaccination using GT198 protein as an antigen in mouse xenograft of GL261 glioma delayed tumor growth and prolonged mouse survival. Together, these findings suggest that GT198-expressing malignant pericytes can give rise to tumor cells through angiogenesis, and serve as a potential source of cells for distant metastasis. Hence, the oncoprotein GT198 has the potential to be a new target in anti-angiogenic therapies in human cancer.

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Section: Introductionmentioning

confidence: 99%

Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis

et al. 2017

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“…From a cancer biology prospective, GT198 regulates stem cells, stimulates angiogenesis [ 34 , 36 ], and induces apoptosis [ 33 ]. From a genetic prospective, the GT198 gene carries germlime and somatic mutations in cancers [ 27 , 28 , 34 ] and in ovarian diseases [ 29 ]. Our current study extends the role of GT198 into a new dimension as a multidrug target, providing further support for GT198 in oncogenesis [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

“…The GT198 protein is originally characterized as a transcriptional coactivator [23,26]. The human GT198 gene carries germline mutations in early-onset breast and ovarian cancer families [27,28], in familial ovarian disease [29], and insufficiencies [30][31][32]. Somatic mutations in GT198 are prevalent and recurrent in the tumor microenvironment of sporadic cancers [27,33].…”

Section: Introductionmentioning

confidence: 99%

GT198 Is a Target of Oncology Drugs and Anticancer Herbs

Pang

Gao

Zhang

et al. 2021

Front. Oral. Health

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Tumor angiogenesis is a hallmark of cancer. Therapeutic drug inhibitors targeting angiogenesis are clinically effective. We have previously identified GT198 (gene symbol PSMC3IP, also known as Hop2) as an oncoprotein that induces tumor angiogenesis in human cancers, including oral cancer. In this study, we show that the GT198 protein is a direct drug target of more than a dozen oncology drugs and several clinically successful anticancer herbs. GT198 is a DNA repair protein that binds to DNA. Using an in vitro DNA-binding assay, we tested the approved oncology drug set VII from the National Cancer Institute containing 129 oncology drugs. Identified GT198 inhibitors include but are not limited to mitoxantrone, doxorubicin, paclitaxel, etoposide, dactinomycin, and imatinib. Paclitaxel and etoposide have higher binding affinities, whereas doxorubicin has higher binding efficacy due to competitive inhibition. GT198 shares protein sequence homology with DNA topoisomerases, which are known drug targets, so that GT198 is likely a new drug target previously unrecognized. To seek more powerful GT198 inhibitors, we further tested several anticancer herbal extracts. The positive anticancer herbs with high affinity and high efficacy are all clinically successful ones, including allspice from Jamaica, Gleditsia sinensis or honey locust from China, and BIRM from Ecuador. Partial purification of allspice using an organic chemical approach demonstrated great feasibility of natural product purification, when the activity is monitored by the in vitro DNA-binding assay using GT198 as a target. Together, our study reveals GT198 as a new targeting mechanism for existing oncology drugs. The study also delivers an excellent drug target suitable for compound identification and natural product purification. In particular, this study opens an opportunity to rapidly identify drugs with high efficacy and low toxicity from nature.

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“…The two mutations carried by the patient were inherited respectively from her biological mother and father. PSMC3IP has previously been linked to hereditary breast and ovarian cancer, as well as causing autosomal recessive POI [8,10,11]. PSMC3IP defects can disrupt estrogen-driven transcription activation of PSMC3IP.…”

Section: Discussionmentioning

confidence: 99%

Two novel biallelic mutations in PSMC3IP in a Chinese patient affected by primary ovarian insufficiency: case report and review of the literature

Mei¹,

Huang²,

Huang³

et al. 2021

Preprint

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Background:Premature ovarian insufficiency (POI) is a heterogeneous condition occurring when a woman experiences a loss of ovarian activity before the age of 40. It is one of the most common reproductive endocrine diseases in women of childbearing age. Here, we investigated the clinical manifestations and genetic features of a Chinese patient affected by POI.Methods: We applied next-generation whole-exome capture sequencing with Sanger direct sequencing to the proband and her clinically unaffected family members. Results: Two novel compound heterozygous mutations were identified in the PSMC3IP gene. The first is a splicing mutation (c.597+1G>T) that was inherited from her father, while the second mutation (c.268G>C p.D90H) was also discovered in her mother and younger sister. The two mutations were co-segregated with the disease phenotype in the family. Conclusions: To our knowledge, this is the first report of PSMC3IP mutations causing POI in the Chinese population. Our findings further support the key role of the PSMC3IP gene in the etiology of POI. However, additional studies are required to explore the underlying molecular mechanisms involved.

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

Cited by 11 publications

References 42 publications

Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis

Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis

GT198 Is a Target of Oncology Drugs and Anticancer Herbs

Two novel biallelic mutations in PSMC3IP in a Chinese patient affected by primary ovarian insufficiency: case report and review of the literature

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