MicroRNA­34b expression enhances chemosensitivity of endometrial cancer cells to paclitaxel.

Aberrant DNA methylation is widely observed in various types of cancer, and expression of microRNAs (miRNAs/miRs) is suppressed by DNA methylation. The present study explored tumor suppressor miRNAs downregulated by DNA methylation in endometrial cancer cells, as the basis of a novel therapeutic approach for endometrial cancer. Among 821 candidate miRNAs, miR­34b was identified as an upregulated miRNA after demethylation treatment in all four endometrial cancer cell lines (HEC­108, SNG­II, Ishikawa and HHUA) examined. miR­34b expression with or without demethylation treatment in cancer cells was confirmed by TaqMan quantitative PCR. MYC and MET, the predicted target genes of miR­34b, were downregulated at both the RNA and protein levels following miR­34b overexpression. Following miR­34b treatment, inhibition of cell growth and invasion, and cell cycle arrest were observed in HEC­108 cells. Sensitivity to paclitaxel was increased in cancer cells with miR­34b overexpression, compared with untreated cancer cells, but this difference was not identified for cisplatin or doxorubicin. In vivo, combination treatment with miR­34b and paclitaxel markedly reduced tumor growth compared with treatment with negative control miRNA and paclitaxel. These data suggest that miR­34b enhances paclitaxel sensitivity in endometrial cancer cells, and that miR­34b and MET are key targets for treatment of endometrial cancer. The present results may contribute to the development of combination treatment with a demethylation agent, miR­34b mimic or MET inhibitor and an anticancer drug.

Erratum: Aurora kinase inhibitors: Potential molecular-targeted drugs for gynecologic malignant tumors (Review).

[This corrects the article DOI: 10.3892/br.2013.91.].

Mutations of RAS genes in endometrial polyps.

Endometrial polyps are common, yet the molecular mechanisms underlying their formation and progression remain unclear. We examined gene mutations possibly related to the pathogenesis of endometrial polyps, as well as to their clinical features. Four premenopausal patients with endometrial polyps, who were not under drug treatment, were recruited. Whole exomes of endometrial polyps and peripheral blood lymphocytes were analyzed by next­generation sequencing, and somatic mutations were derived by subtraction. Then, 35 samples of endometrial polyps and 12 samples of atypical polypoid adenomyoma were newly recruited to validate the identified mutations by polymerase chain reaction­reverse sequence specific oligonucleotide method. The mutations were also analyzed in separate stromal and glandular components of the polyps after laser­capture microdissection. Whole exome sequencing revealed that KRAS mutations were the only type of mutation detectable in multiple cases (2/4). Targeted mutation analysis revealed that 16 of 35 samples (45.7%) of endometrial polyps harbored RAS mutations. Mutation­positive cases exhibited a significantly higher number of endometrial polyps (3.25±2.70 vs. 1.74±0.87, P=0.045). Laser­capture microdissection in NRAS­mutated endometrial polyps revealed that both stromal and glandular components harbored RAS mutations. There was no RAS mutation in 12 samples of atypical polypoid adenomyoma. This is the first report demonstrating that pathogenic RAS mutations are frequent in non­treated endometrial polyps. RAS mutations may have an important role in tumorigenesis and in the formation of multiple endometrial polyps.

Current status of uterine regenerative medicine for absolute uterine factor infertility.

Though assisted reproduction technology has been developed, a treatment for absolute uterine factor infertility (AUFI), such as defects in the uterus, has not yet been established. Regenerative medicine has been developed and applied clinically over recent years; however, whole solid organs still cannot be produced. Though uterine regeneration has the potential to be a treatment for AUFI, there have been only a few studies on uterine regeneration involving the myometrium in vivo. In the present report, those relevant articles are reviewed. A literature search was conducted in PubMed with a combination of key words, and 10 articles were found, including nine in rat models and one in a mouse model. Of these studies, eight used scaffolds and two were performed without scaffolds. In four of these studies, scaffolds were re-cellularized with various cells. In the remaining four studies, scaffolds were transplanted alone, or other structures were used. Though the methods differed, the injured uterus recovered well, morphologically and functionally, in every study. Only 10 articles were relevant to our investigation, but the results were favorable, if limited to partial regeneration. Recently, uterus transplantation (UTx) has been investigated as a treatment for AUFI. However, UTx has many problems in the medical, ethical and social fields. Though the artificial uterus was also researched and some improvements in this technology were reported, it will take long time for this to reach a clinically applicable stage. Though the results of uterine regeneration studies were promising, these studies were conducted using animal models, so further human studies and trials are needed.

Synchronous endometrial and ovarian cancer in Lynch syndrome with a MSH2 germline mutation: A case report.

Synchronous endometrial and ovarian cancer (SEOC) is a rare entity among gynecological cancers, which exhibits endometrioid histology in its early stages and generally has a good prognosis. However, diagnosis is difficult and recent reports have demonstrated that most clinically diagnosed cases of SEOC have clonally related cancers, indicating metastatic cancer. The association of SEOC with Lynch syndrome is also not clearly understood. We herein present the case of a 41-year-old SEOC patient with MSH2 mutation. The endometrial cancer was an endometrioid adenocarcinoma and the ovarian cancer was mainly endometrioid, but also included a clear cell carcinoma with a borderline clear cell adenofibromatous component, indicating primary ovarian cancer. Both tumors exhibited microsatellite instability (MSI) and loss of expression of MSH2 and MSH6. The patient had a family history of colorectal and gastric cancers. Genetic analysis revealed a germline mutation in exon 6 of MSH2 (c.1042C>T, p.Gln348*) and the patient was diagnosed with Lynch syndrome. This MSH2 mutation has only been registered in one case in the InSiGHT variant databases and has not been reported in a gynecological tumor or SEOC to date. This case is a rare example of a patient with genetically diagnosed Lynch syndrome who also developed SEOC. This synchronous cancer is not common, but it may be caused by Lynch syndrome. Testing for MSI and immunohistochemistry for mismatch repair deficiency is necessary in cases with suspected SEOC.

Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.

OBJECTIVE: Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. METHODS: The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM5 were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. RESULTS: Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM5, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. CONCLUSION: This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients.

Recent findings on epigenetic gene abnormalities involved in uterine cancer.

Selective aberrant genetic effects that do not depend on abnormal DNA sequences are referred to as epigenetic abnormalities and are involved in carcinogenesis. In uterine cancer, various genes involved in apoptosis, cell cycle, DNA repair, cell proliferation and cell adhesion are abnormally methylated, resulting in gene silencing. Reversal of such epigenetic abnormalities in cancer cells is a potential strategy for cancer therapy, and studies on epigenetic abnormalities and treatment methods in uterine cancer are in progress. These include the evaluation of 5-hydroxymethylcytosine, which is present in cancer tissues at lower levels compared with those in normal tissues, as a prognostic marker in cervical cancer; combination therapy with 5-azacytidine and cisplatin; combination treatment focusing on tumor necrosis factor-related apoptosis-inducing ligand in cervical cancer; studies focusing on DNA mismatch repair in endometrial cancer; and use of a demethylating agent to reactivate tumor suppressor genes and inhibit tumor proliferation. Detection of epigenetic changes using biomarkers may be used for histological classification, evaluation of disease progression and identification of compounds that are able to modulate epigenetic changes and may be useful for uterine cancer treatment.

Aberrant chromatin remodeling in gynecological cancer.

Epigenetic regulatory mechanisms are a current focus in studies investigating cancer. Chromatin remodeling alters chromatin structure and regulates gene expression, and aberrant chromatin remodeling is involved in carcinogenesis. AT-rich interactive domain-containing protein 1A (ARID1A) and SWItch/sucrose non-fermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 are remodeling factors that are mutated in numerous types of cancer. In gynecological cancer, ARID1A mutations have been identified in 46-57% of clear cell carcinoma and 30% of endometrioid carcinoma. Mutations of chromodomain helicase, DNA-binding protein 4 have been detected in 17-21% of endometrial serous cancer, and mutations of ARID1A and mixed-lineage leukemia 3 occur in 36 and 27% of uterine carcinosarcoma, respectively. These data suggest that aberrant chromatin remodeling is a potential cause of cancer, and have led to the development of novel proteins targeting these processes. Additional accumulation of information on the mechanisms of chromatin remodeling and markers for these events may promote personalized anticancer therapies.

New use of microsatellite instability analysis in endometrial cancer.

The increasing incidence of obesity and diabetes due to changes in diet, earlier menarche, delayed menopause, late marriage, and declining birth rate have resulted in an increase in the number of endometrial cancer cases over the last few decades. Although surgical therapy is sufficient for early endometrial cancer, there is no effective therapy for patients with advanced and recurrent endometrial cancer. The oncogenic mechanism of endometrial cancer involves microsatellite instability (MSI) caused by dysfunction of DNA mismatch repair genes in 30% of patients. Immune checkpoint inhibitors, including anti-programmed death (PD)-1 and anti-PD-ligand 1 antibodies, are of interest as novel anticancer drugs; however, these drugs are currently expensive, and there is a need to select patients who will benefit from their use. The use of MSI analysis as a predictive biomarker for the therapeutic efficacy of these drugs may be useful for reducing the costs of drug therapy.

Genome-wide DNA methylation sequencing reveals miR-663a is a novel epimutation candidate in CIMP-high endometrial cancer.

Aberrant DNA methylation is widely observed in many cancers. Concurrent DNA methylation of multiple genes occurs in endometrial cancer and is referred to as the CpG island methylator phenotype (CIMP). However, the features and causes of CIMP-positive endometrial cancer are not well understood. To investigate DNA methylation features characteristic to CIMP-positive endometrial cancer, we first classified samples from 25 patients with endometrial cancer based on the methylation status of three genes, i.e. MLH1, CDH1 (E-cadherin) and APC: CIMP-high (CIMP-H, 2/25, 8.0%), CIMP-low (CIMP-L, 7/25, 28.0%) and CIMP-negative (CIMP(-), 16/25, 64.0%). We then selected two samples each from CIMP-H and CIMP(-) classes, and analyzed DNA methylation status of both normal (peripheral blood cells: PBCs) and cancer tissues by genome-wide, targeted bisulfite sequencing. Genomes of the CIMP-H cancer tissues were significantly hypermethylated compared to those of the CIMP(-). Surprisingly, in normal tissues of the CIMP-H patients, promoter region of the miR-663a locus is hypermethylated relative to CIMP(-) samples. Consistent with this finding, miR-663a expression was lower in the CIMP-H PBCs than in the CIMP(-) PBCs. The same region of the miR663a locus is found to be highly methylated in cancer tissues of both CIMP-H and CIMP(-) cases. This is the first report showing that aberrant DNA methylation of the miR-663a promoter can occur in normal tissue of the cancer patients, suggesting a possible link between this epigenetic abnormality and endometrial cancer. This raises the possibility that the hypermethylation of the miR-663a promoter represents an epimutation associated with the CIMP-H endometrial cancers. Based on these findings, relationship of the aberrant DNA methylation and CIMP-H phenotype is discussed.

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer.

Cancer typically develops due to genetic abnormalities, but a single gene abnormality cannot completely account for the onset of cancer. The Cancer Genome Atlas (CGA) project was conducted for the cross-sectional genome-wide analysis of numerous genetic abnormalities in various types of cancer. This approach has facilitated the identification of novel AT-rich interaction domain 1A gene mutations in ovarian clear cell carcinoma, frequent tumor protein 53 (TP53) gene mutations in high-grade ovarian serous carcinoma, and Kirsten rat sarcoma and B-rapidly accelerated fibrosarcoma proto-oncogene, serine/threonine kinase gene mutations in low-grade ovarian serous carcinoma. Genome-wide analysis of endometrial cancers has led to the establishment of four subgroups: Polymerase ultramutated, microsatellite instability hypermutated, genome copy-number low and genome copy-number high. These results may facilitate the improvement of the prediction of patient prognosis and therapeutic sensitivity in various types of gynecologic cancer. The enhanced use of currently available therapeutic agents and the development of novel drugs may be facilitated by the novel classification of ovarian cancer based on TP53 mutations, the efficacy of poly (ADP-ribose) polymerase inhibitors for tumors with breast cancer 1/2 mutations and the effect of phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin inhibitors for tumors with mutations in the PI3K/protein kinase B signaling pathway. Important results have been revealed by genome-wide analyses; however, the pathogenic underlying mechanisms of gynecologic cancer will require further studies and multilateral evaluation using epigenetic, transcriptomic and proteomic analyses, in addition to genomic analysis.

Carcinoma of the lower uterine segment diagnosed with Lynch syndrome based on MSH6 germline mutation: A case report.

Endometrial cancer in the lower uterine segment (LUS) is associated with Lynch syndrome with MLH1 or MSH2 germline mutation. Here, we report a case of carcinoma of the LUS diagnosed with Lynch syndrome based on MSH6 germline mutation in a 46-year-old woman with abnormal vaginal bleeding. She had had rectal cancer at age 39 with a family history of colon cancer (father, 75 years), pancreatic cancer (paternal grandmother, 74 years), and colon cancer (maternal grandmother, 85 years). Magnetic resonance imaging showed a tumor in the LUS. Endometrial biopsy revealed endometrioid adenocarcinoma G1. As her cancer history met the revised Bethesda criteria, we examined microsatellite instability and the result was negative, but loss of the MSH6 expression was detected by immunohistochemistry. Genetic testing revealed deleterious germline mutation of MSH6, which was compatible with Lynch syndrome. To our knowledge, this is the first case of endometrial carcinoma of the LUS with MSH6 germline mutation.

Differential micro ribonucleic acid expression profiling in ovarian endometrioma with leuprolide acetate treatment.

AIM: Micro ribonucleic acids (miRNAs) play an important pathological role in endometriosis. Leuprolide acetate, an analog of gonadotropin-releasing hormone, is widely used to treat endometriosis; however, the molecular mechanisms involved in endometriotic tissue regression remain unclear. We performed miRNA expression profiling of clinical ovarian endometrioma to obtain insight into the effects of leuprolide acetate treatment. METHODS: We obtained clinical samples from nine normal eutopic endometrium, eight ovarian endometriotic, and 12 leuprolide acetate-treated endometriotic tissues. We compared the miRNA expression profiles of the three groups by performing TaqMan Array MicroRNA Card and bioinformatic analysis. RESULTS: Two miRNAs, miR-939 and miR-154, were upregulated in endometriotic tissue and downregulated in leuprolide acetate-treated endometriotic tissue. Five miRNAs (miR-146a, miR-142-3p, miR-136*, miR-125b-1* and miR-15b*) were unchanged in endometriotic tissue but were upregulated under leuprolide acetate treatment. Ingenuity pathway analysis using predicted target genes for the seven identified miRNAs suggested the involvement of a range of pathways, including axonal guidance, bone morphogenetic protein, phosphatase and tensin homolog and nitric oxide signaling; molecular mechanisms of cancer; and the adipogenesis and signal transducer and activator of transcription 3 (STAT3) pathways. CONCLUSIONS: To our knowledge, this is the first report profiling the miRNAs of endometrioma under leuprolide acetate treatment. The expression of seven miRNAs was modulated, concomitant with the disease state. This result gives new insight into the effects of leuprolide acetate treatment. Further investigation using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry will allow us to validate the results of this study and to explore new therapeutic targets and biomarkers of endometriosis.

Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis.

Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%)-1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.

Metformin: A candidate for the treatment of gynecological tumors based on drug repositioning.

Metformin is a first-line drug used for the treatment of type 2 diabetes. Recently, metformin has been reported to reduce the carcinogenic risk and inhibit tumor cell growth in glioma and breast cancer. The anticancer action of metformin involves the enhancement of phosphorylation of liver kinase B1, activation of adenosine monophosphate-activated protein kinase and inhibition of mammalian target of rapamycin, which reduces cell growth. Metformin is anticipated to exert antitumor effects in gynecological cancer, and its efficacy for the treatment of endometrial, breast and ovarian cancer has been suggested in preclinical studies and clinical trials. Although the effect of metformin on cervical cancer remains to be examined in clinical trials, its antitumor effects have been reported in preclinical studies. Thus, the use of metformin for the treatment of gynecological cancer may become a successful example of drug repositioning, following establishment of the drug's antitumor effects, risk evaluation, screening and validation of efficacy.

ARID1A gene mutation in ovarian and endometrial cancers (Review).

The AT-rich interacting domain­containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome­wide analyses with next­generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis­associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis­associated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis­associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular­targeted drug can inhibit proliferation of ARID1A­mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis, to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development, survival and progression of cancer cells.

MicroRNAS in endometrial cancer: recent advances and potential clinical applications.

Endometrial cancer is a common malignant gynecological tumor, but there are few biomarkers that are useful for early and accurate diagnosis and few treatments other than surgery. However, use of microRNAs (miRNAs) that induces gene downregulation in cells may permit effective and minimally invasive diagnosis and treatment. In endometrial cancer cells, expression levels of miRNAs including miR-185, miR-210 and miR-423 are upregulated and those of miR-let7e, miR-30c and miR-221 are downregulated compared to normal tissues, and these miRNAs are involved in carcinogenesis, invasion and metastasis. miRNAs with expression changes such as miR-181b, miR-324-3p and miR-518b may be used as prognostic biomarkers and transfection of miR-152 may inhibit cancer growth. However, most current studies of miRNAs are at a basic level and further work is needed to establish clinical applications targeting miRNAs.

Differential mRNA expression profiling in ovarian endometriotic tissue with versus without leuprolide acetate treatment.

AIM: Leuprolide acetate, an analog of gonadotropin-releasing hormone (GnRH), regresses endometriotic tissue and reduces pain, resulting in clinical improvement upon treatment. The molecular mechanisms involved in the regression of endometriotic tissue, however, remain to be elucidated. In this study, we performed genome-wide gene expression profiling of clinical specimens of ovarian endometrioma to obtain insight into the effects of leuprolide acetate treatment. METHODS: We obtained clinical samples from nine normal eutopic endometrium tissues, eight ovarian endometriotic tissues, and 12 leuprolide acetate-treated endometriotic tissues. We compared the gene expression profiles of the three groups using Affymetrix GeneChip Human genome arrays and bioinformatic analysis, including molecular concept analysis. RESULTS: Leuprolide acetate-treated endometriotic tissue showed downregulated genes associated with the biological functions of steroid hormone regulation, cell proliferation, inflammation, and intracellular signaling. These genes included PTGDS, GRP, APLP2, PLTP, and FGFRL1. In contrast, genes upregulated by leuprolide acetate treatment were associated with cell growth inhibition and apoptosis. These genes included CARD11 and USP18. CONCLUSIONS: These preliminary results based on GeneChip analysis suggest that leuprolide acetate treatment induces a modulation of gene expression that allows for cooperative alterations in disease state. This study gives new insight into the effects of leuprolide acetate treatment. Further investigations with quantitative reverse transcription-polymerase chain reaction and immunohistochemistry are needed to validate this study and to explore new therapeutic targets and biomarkers of endometriosis.

Risk-reducing surgery in hereditary gynecological cancer: Clinical applications in Lynch syndrome and hereditary breast and ovarian cancer.

Risk-reducing surgery (RRS) is defined as a prophylactic approach with removal of organs at high risk of developing cancer, which is performed in cases without lesions or absence of clinically significant lesions. Hereditary gynecological cancers for which RRS is performed include hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. For HBOC, RRS in the United States (US) is recommended for women with mutations in the breast cancer susceptibility (BRCA)1 and BRCA2 genes and bilateral salpingo-oophorectomy (BSO) is generally performed. This procedure may reduce the risk of breast, ovarian, Fallopian tube and primary peritoneal cancer, although ovarian deficiency symptoms occur postoperatively. For Lynch syndrome, RRS in the US is considered for postmenopausal women or for women who do not desire to bear children and BSO and hysterectomy are usually performed. This approach may reduce the risk of endometrial and ovarian cancer, although ovarian deficiency symptoms also occur. For RRS, there are several issues that must be addressed to reduce the risk of cancer development in patients with HBOC or Lynch syndrome. To the best of our knowledge, this is the first review to discuss RRS with a focus on hereditary gynecological cancer.

Drug repositioning for gynecologic tumors: a new therapeutic strategy for cancer.

The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokinetics are established and to expand the therapeutic range of the drug to another disease. Such drug discovery can be performed at low cost and in the short term based on the results of previous clinical trials. New drugs for gynecologic tumors may be found by drug repositioning. For example, PPAR ligands may be effective against ovarian cancer, since PPAR activation eliminates COX-2 expression, arrests the cell cycle, and induces apoptosis. Metformin, an antidiabetic drug, is effective for endometrial cancer through inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growth factor-1 due to AMPK activation. COX-2 inhibitors for cervical cancer may also be examples of drug repositioning. PGE2 is induced in the arachidonate cascade by COX-2. PGE2 maintains high expression of COX-2 and induces angiogenic factors including VEGF and bFGF, causing carcinogenesis. COX-2 inhibitors suppress these actions and inhibit carcinogenesis. Combination therapy using drugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions. Thus, drug repositioning may become a key approach for gynecologic cancer in drug discovery.