BRCA1 and p53 protein expression in cultured ovarian surface epithelial cells derived from women with and without a BRCA1 germline mutation

Aim Mutations in the BRCA1 and TP53 genes are early genetic events leading to (hereditary) ovarian carcinoma. The human ovarian surface epithelium (OSE) is considered the tissue of origin of at least a subset of these tumours. Therefore, OSE cell cultures derived from women harbouring BRCA1 germline mutations can be a potential model to study hereditary ovarian carcinogenesis. In fact, previous in vitro studies indicate phenotypical differences between OSE from women with and without such germline mutations. Therefore, we have assessed whether differences in the expression of BRCA1 and p53 proteins in cultured OSE cells could contribute to these observations.Study design Thirty-two OSE cultures derived from women harbouring a BRCA1 mutation (Predisposed OSE [POSE]) and ten cultures from women without a cancer predisposition (Non predisposed OSE [NPOSE]) were grown under standard conditions. Immunocytochemistry was performed to assess the expression of the BRCA1- and p53 proteins. Ki67 immunocytochemical expression was assessed to determine possible differences in cell cycle status between the two groups. In addition, to study whether wild type p53 was expressed, induction of p53 by cis-platinum was assessed by Western blot.Results On the basis of Ki67 expression, three different groups were analyzed. In the group with all cultures that expressed Ki67 no significant difference was observed in BRCA1 (P = 0.19) and p53 expression (P = 0.09). In the group with moderate to high Ki67 expression no difference in BRCA1 expression (P = 0.50) was observed. However, p53 expression was significantly lower in the case group (P = 0.01). The same observation for p53 was made in the group with only high Ki67 expression (P = 0.02). Furthermore, the expression of both BRCA1 and p53 positively correlates with Ki67 expression. In POSE and NPOSE, p53 was induced by cis-platinum to a similar extent.Conclusion Our study indicates differences in the expression of p53, but not in the expression of BRCA1 between POSE and NPOSE. In addition, our findings do suggest the absence of losses of the wild type BRCA1 and p53 genes in the studied OSE cultures. This indicates that losses in these genes cannot account for observed differences in phenotypical traits between POSE and NPOSE, but that differences in levels of p53 might contribute.     

Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma

Objective

BRCA-associated and sporadic ovarian cancers have different pathologic and clinical features. Our goal was to determine if BRCA mutation status is an independent predictor of residual tumor volume following primary surgical cytoreduction.

Methods

We conducted a retrospective analysis of patients with FIGO stage IIIC-IV high-grade serous ovarian cancer classified for the presence or absence of germline BRCA mutations. The primary outcome was tumor-debulking status categorized as complete gross resection (0 mm), optimal but visible disease (1-10 mm), or suboptimal debulking (> 10 mm) following primary surgical cytoreduction. Overall survival by residual tumor size and BRCA status was also assessed as a secondary endpoint.

Results

Data from 367 patients (69 BRCA mutated, 298 BRCA wild-type) were analyzed. Rate of optimal tumor debulking (0-10 mm) in BRCA wild-type and BRCA-mutated patients were 70.1% and 84.1%, respectively (P = 0.02). On univariate analysis, increasing age (10-year OR, 1.33; 95% CI, 1.07-1.65; P = 0.01) and wild-type BRCA status (OR, 0.47; 95% CI, 0.23-0.94, P = 0.03) were both significantly associated with suboptimal surgical outcome. On multivariate analysis, BRCA mutation status was no longer associated with residual tumor volume (OR, 0.63; 95% CI, 0.31-1.29; P = 0.21) while age remained a borderline significant predictor (10-year OR, 1.25; 95% CI, 1.01-1.56; P = 0.05). Both smaller residual tumor volume and mutant BRCA status were significantly associated with improved overall survival.

Conclusion

BRCA mutation status is not associated with the rate of optimal tumor debulking at primary surgery after accounting for differences in patient age. Improved survival of BRCA carriers is unlikely the result of better surgical outcomes but instead intrinsic tumor biology.     

Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer

Background

The heritable fraction of ovarian cancer exceeds that of any other common adult cancer. Most inherited cases of ovarian cancer are due to a germline mutation in BRCA1 or BRCA2. It is important to have an accurate estimate of the proportion of ovarian cancer patients who carry a mutation and the specific factors which predict the presence of a mutation.

Methods

We tested a population-based series of 1342 unselected patients diagnosed with invasive ovarian cancer between 1995-1999 and 2002-2004 in Ontario, Canada, for germline mutations in BRCA1 and BRCA2. The two genes were tested in their entirety, using a range of techniques, including multiplex ligation-dependent probe amplification (MLPA).

Results

Among the 1342 women, 176 women carried a mutation (107 in BRCA1, 67 in BRCA2, and two in both genes) for a combined mutation frequency of 13.3%. Seven deletions were identified using MLPA (3.9% of all detected mutations). The prevalence of mutations was particularly high among women diagnosed in their forties (24.0%), in women with serous ovarian cancer (18.0%) and women of Italian (43.5%), Jewish (30.0%) or Indo-Pakistani origin (29.4%). A mutation was seen in 33.9% of women with a first-degree relative with breast or ovarian cancer and in 7.9% of women with no first-degree relative with breast or ovarian cancer. No mutation was seen in women with mucinous carcinoma.

Conclusions

BRCA1 and BRCA2 mutations are common in women with invasive ovarian cancer. All women diagnosed with invasive non-mucinous ovarian cancer should be considered to be candidates for genetic testing.     

Germline mutations of BRCA1 and BRCA2 in Korean sporadic ovarian carcinoma

OBJECTIVES: Mutations in the BRCA1 and BRCA2 genes predispose women to ovarian and/or breast cancer. The contribution of BRCA1 and BRCA2 mutations to ovarian cancer in Korean women remains to be elucidated. In addition, genetic polymorphisms may affect not only cancer development but also cancer progression and, as a result, could influence cancer phenotypes. The purposes of this study were, first, to investigate the presence of BRCA1 and BRCA2 mutations in women with ovarian cancer who were unselected for family history and, second, to evaluate the relationship between ovarian cancer susceptibility gene polymorphisms and clinicopathological features. METHODS: We studied 37 women who were diagnosed with epithelial ovarian cancer and treated at the Yonsei University Hospital between August 2002 and March 2004. Genomic DNA was analyzed for BRCA mutations using a PCR-DHPLC-sequencing method. The relationship between ovarian cancer susceptibility gene polymorphisms and clinicopathological features was examined. RESULTS: Most mutations of BRCA1 and BRCA2 associated with ovarian and/or breast cancer result in truncated proteins. We found one frameshift mutation in BRCA1 (3746insA) that led to premature termination. The patient had no family history of breast or ovarian cancer. There was no relationship between ovarian cancer susceptibility gene polymorphisms and clinicopathological features. CONCLUSION: Our results were consistent with the hypothesis that BRCA1 and BRCA2 mutations have a limited role in sporadic ovarian carcinogenesis in the Korean population. Furthermore, polymorphisms of certain, selected ovarian cancer susceptibility genes were not associated with the clinicopathological phenotypes of ovarian cancer.     

Efficacy of screening women at high risk of hereditary ovarian cancer: results of an 11-year cohort study

Abstract.   Gaarenstroom KN, van der Hiel B, Tollenaar RAEM, Vink GR, Jansen FW, van Asperen CJ, Kenter GG. Efficacy of screening women at high risk of hereditary ovarian cancer: results of an 11-year cohort study. Int J Gynecol Cancer 2006; 16(Suppl. 1): 54–59.
The outcome of screening and prophylactic surgery in 269 women at high risk of hereditary ovarian cancer is reported. Screening was performed using transvaginal ultrasound and serum CA125 testing. Mean follow-up was 26 months (583 person-years). A total of 113 (42%) of 269 women had a pathogenic BRCA1 or BRCA2 mutation, and 127 (47%) of 269 women underwent salpingo-oophorectomy. No occult cancers were found. In eight women having both elevated CA125 levels and abnormal ultrasound findings, a malignancy was found. Four of these cancers (one borderline, one stage Ia, one stage IIIb, and one stage IIIc ovarian or peritoneal cancer) were detected at the first screening visit. One stage IIIb and one stage IIIc cancer were detected at the second screening visit after 12 months, and two interval stage IIIc and IV cancers were detected 8 and 10 months after the first screening visit. No peritoneal carcinoma was found among those 114 women who underwent bilateral salpingo-oophorectomy with normal or benign pathology results, after a mean follow-up of 16 months (152 person-years). We conclude that the efficacy of screening women at high risk of ovarian cancer seems poor because the majority of cancers were detected at an advanced stage.     

Screening for ovarian cancer by transvaginal ultrasound and serum CA125 measurement in women with a familial predisposition: a prospective cohort study

OBJECTIVE: This study evaluates the accuracy of transvaginal ultrasound (TVUS) in combination with CA125 to detect ovarian cancer in women at hereditary risk for ovarian cancer. METHODS: A semi-annual surveillance protocol comprising CA125 measurement and TVUS was offered to 676 women including 85 BRCA mutation carriers. Surgical intervention was performed if TVUS revealed a suspicious cyst or if elevated CA125 levels or cystic lesions persisted in two consecutive examinations. RESULTS: Ten women underwent histological verification that revealed one serous cystadenocarcinoma stage Ic. No interval ovarian cancer occurred. The specificity of surgical intervention reached 98.7% (95% confidence interval (CI): 97.5% to 99.3%) and a positive predictive value (PPV) of 10% (95% CI: 1.8% to 40.4%). CONCLUSION: The low PPV is due to the unexpectedly low incidence of ovarian cancer. Large scale investigations including details on potential confounders and modifiers are needed to further evaluate accuracy and effectiveness of ovarian cancer screening for women at high risk.     

Artificial neural network computer prediction of ovarian malignancy in women with adnexal masses.

OBJECTIVE: Assessment of the usefulness of a neural model to predict which ovarian tumors are malignant. METHOD: Age, menopausal status, body mass index, grayscale and Doppler ultrasonographic features, as well as levels of specific markers (CA 125, tissue polypeptide specific antigen) were examined in 686 women with adnexal masses. The probability of malignancy was calculated using an artificial neural network software and the diagnostic efficiency of the received model was estimated using a receiver-operating characteristics (ROC) curve. RESULT: Of the 686 women, 431 (62.8%) had a benign and 255 (37.2%) had a malignant ovarian tumor. The significant malignancy predictors are age, menopausal status, maximum tumor diameter, internal wall structure of tumor, presence of septa and/or solid elements, tumor location, location of vessels, and blood flow indexes. The best network provided 96.0% sensitivity and 97.7% specificity. The area under the curve for the received model was 0.9716. CONCLUSIONS: An artificial neural network model based on clinical and ultrasonographic data allows to calculate the probability of tumor malignancy.     

BRCA1 and BRCA2 mutations among ovarian cancer patients from Colombia

Objective

The contribution of BRCA1 and BRCA2 mutations to ovarian cancer in Colombia has not yet been explored. Five founder mutations have been identified in two previous studies of breast cancer patients in the Bogota region [1,2]. It is important that the frequency of mutations be established among unselected cases of ovarian cancer in order to estimate the genetic burden of this cancer in Colombia and to plan genetic and preventive services.

Methods

We enrolled 100 unselected women with ovarian cancer from the Bogota region, and from northern and southern central regions of Colombia. A detailed family history was obtained from each patient and a blood sample was processed for DNA analysis. DNA quality was adequate for BRCA testing for 96 women. Mutations in BRCA1 and BRCA2 were sought using a Hispanic BRCA mutation testing panel. All mutations were confirmed by direct sequencing.

Results

Fifteen mutations were identified (two in BRCA2 and thirteen in BRCA1) representing 15.6% of the total (95% CI: 7.8% to 21.3%). Among the 15 mutation-positive families there were nine breast-ovarian cancer families, one gastric cancer family, one prostate cancer family, three uterine cancer families, and one family with no history of cancer. A single founder mutation in BRCA1 (3450del4) was seen in 11 patients.

Conclusion

In summary, BRCA1 founder mutations are common in Colombian women with ovarian cancer. Approximately 11.5% of all ovarian cancer cases in the Bogota region are attributable to a single BRCA1 founder mutation.     

There is no decision to make: experiences and attitudes toward treatment-focused genetic testing among women diagnosed with ovarian cancer

Objective

There is growing evidence that the BRCA mutation status of women newly diagnosed with ovarian cancer may be used to make treatment recommendations in the future. This qualitative study aimed to assess women's attitudes and experiences toward treatment-focused genetic testing (TFGT).

Methods

Women (N = 22) with ovarian cancer who had either (i) advanced disease and had previously had TFGT (n = 12) or (ii) had a recent ovarian cancer diagnosis and were asked about their hypothetical views of TFGT (n = 10), were interviewed in-depth.

Results

This study demonstrates that patients diagnosed with ovarian cancer found the concept of TFGT acceptable with the primary motivation for genetic testing being to increase their treatment options. Women reported that there was no decision to make about TFGT, and the advantages of TFGT were perceived to outweigh the disadvantages. Many women described elements of resilience and active coping, in the context of hypothetical and actual TFGT.

Conclusions

Resilience and active coping strategies are important factors that warrant investigation as potential moderators of psychological distress in future prospective studies exploring the optimal way of offering BRCA genetic testing to women newly diagnosed with ovarian cancer, and to assess the impact of TFGT upon patients' survival, psychological distress, and quality of life.     

Analysis of the time interval between diagnoses in women with double primary breast and ovarian or primary peritoneal cancers

OBJECTIVES: The time interval between diagnoses of breast and epithelial ovarian cancer is not well established in women with dual primary tumors of both organ sites. Our goals were to examine the time interval between diagnoses and identify any relationship to clinicopathologic factors. METHODS: We identified 49 patients who developed both cancers. These patients were divided into two groups: group 1 patients developed breast cancer first, group 2 patients had ovarian before breast cancer. The risk of a BRCA1 or BRCA2 mutation in our study subjects was estimated using the BRCAPRO. Parameters were compared using either the chi(2) or the Kruskal-Wallace test. RESULTS: There were 26 and 23 patients in groups 1 and 2, respectively. The mean time interval was longer in group 2 (86 vs. 45 months; P = 0.013). Median PFS and OS were longer in group 2 for both cancers [PFS: 161 vs. 61 months for breast (P = 0.85) and 132 vs. 39 months for ovarian (P = 0.019); OS: 250 vs. 115 months for breast (P = 0.77) and 277 vs. 42 months for ovarian (P = 0.0013)]. OS was longer in group 2 for both cancers combined 217 vs. 115 (P = 0.026). The estimated risk of BRCA mutation was at least 20% in the majority of the patents. CONCLUSIONS: Our data indicates that the time interval between the diagnosis of breast and ovarian carcinomas is 4 years. In contrast, the time interval between the diagnosis of ovarian and breast carcinomas is 7 years. These results could be useful in counseling women at risk.     

Gonadotropins and ovarian carcinogenesis: a new era of basic research and its clinical implications

The possible relationship between gonadotropins and ovarian carcinoma development has received much attention, and in recent years, great progress has been made in basic and epidemiologic research about this issue. Gonadotropins sensitivity in the ovarian surface epithelium (OSE) and in a subset of ovarian carcinomas has been established in vivo and in vitro. Gonadotropins have been shown to induce various biologic actions in the OSE and ovarian carcinoma cells, such as changes in cell proliferation, apoptosis, cell adhesion, and chemosensitivity. These basic studies strongly suggest that gonadotropins are involved in the development and progression of ovarian carcinoma. In contrast, although earlier studies showed a significant risk of infertility therapy for ovarian carcinoma development, subsequent studies reported only slightly increased or no significant increased risk of gonadotropin stimulation and/or assisted reproductive technologies for ovarian carcinoma development. Therefore, the association between ovarian stimulation and ovarian carcinoma remains controversial. Nevertheless, since development of ovarian carcinoma in infertile women during infertility treatment is a serious concern for gynecologists, this review also covers important points for clinical practice, especially the issue of early detection of ovarian carcinoma.     

Experiments with tissue cultures from a human ovarian serous cystadenocarcinoma producing cancer antigen 125 (CA125), tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA)

Summary The patient was a 57-year-old woman with ovarian serous cystadenocarcinoma in FIGO clinical stage IV. Cancer antigen 125 (CA 125), tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA) were immunohistochemically demonstrated in tumor cells, and the variations of serum CA125 and TPA levels reflected the clinical course. The tumor tissue obtained at exploratory laparotomy was minced with scissors, and transplanted subcutaneously into female nude mice for in vivo maintenance. The tumor cells from 5th generation nude mice were dispersed in Eagle's minimal essential medium supplemented with 10% fetal calf serum, and incubated in Falcon tissue culture dishes at 37°C in 5% CO₂ in air for in vitro maintenance. The results were as follows: Histopathologically the tumor transplanted into nude mice showed a cystadenocarcinoma, which closely resembled the original human tumor. Immunohistochemically CA125, TPA and CEA were demonstrated in the tumor transplanted into nude mice as well as in the original human tumor. From the growth curve in nude mice, the doubling time was estimated to be about 3.5 days. Serum TPA levels in nude mice were increased in proportion to the tumor growth after transplantation, but serum levels CA125 and CEA were normal. The concentrations of CA125 and TPA were increased in the conditioned media compared with the control media, although the elevated values were decreased with subsequent passages. CEA concentrations in the conditioned media were unchanged.     

74例上皮性卵巢癌患者BRCA基因突变状况及临床意义分析

目的： 统计上皮性卵巢癌（EOC）患者的胚系乳腺癌易感基因（BRCA）致病突变情况,分析其与临床病理特征的关系。方法： 收集2017年1月—2020年1月在天津市中心妇产科医院诊治的EOC患者的胚系BRCA 基因检测情况,并对BRCA基因致病突变与患者临床病理资料进行分析。结果： 74例EOC患者中BRCA1突变18例（24.3%）,BRCA2突变7例（9.5%）,主要突变方式包括框移突变15例,无义突变5例,突变主要集中在外显子编码区（CDS9和CDS10）。BRCA基因突变组和BRCA基因野生组患者的临床分期、组织病理学类型、淋巴结转移、血清CA-125水平、恶性肿瘤家族史进行比较,差异均无统计学意义（P>0.05）。BRCA基因突变组患者无复发生存期（RFS）长于BRCA基因野生组,差异有统计学意义（Z=-1.931,P=0.027）;2组患者遗传性乳腺癌卵巢癌综合征家族史（HBOC家族史）率比较差异有统计学意义（χ² =4.059,P=0.044）。结论： 有HBOC家族史的EOC患者的家系女性成员进行BRCA基因检测是筛查卵巢癌高危患者的有效手段。     

Comparison of clinical outcomes of patients with clear cell and endometrioid ovarian cancer associated with endometriosis to papillary serous carcinoma of the ovary

Objective

The aim of this investigation was to compare outcomes of patients with clear cell carcinoma (CCC) and endometrioid carcinoma (EC) of the ovary associated with endometriosis to patients with ovarian papillary serous carcinoma (PSC).

Methods

Patients with CCC and EC of the ovary associated with endometriosis were identified and matched by age and stage to PSC controls. Student's t test and chi square test were used to analyze continuous and categorical data. The Kaplan–Meier method was used for survival analysis.

Results

67 cases associated with endometriosis were identified, of which 45 were arising in endometriosis. Cases were matched to 134 PSC controls. 27 patients with tumors associated with endometriosis presented at stage I (40.3%), 27 at stage II (40.3%), ten at stage III (14.9%) and three at stage IV (4.5%). There was no difference in rate of optimal cytoreduction or response to chemotherapy in cases vs. PSC controls. There was a significant increase in synchronous endometrial cancer in tumors associated with endometriosis compared to PSC (25.4% vs. 3.7%; P < 0.001). 18 cases (26.9%) had recurrent disease vs. 55 (41%) controls (P = 0.03). The 5-year disease-free survival (DFS) and overall survival (OS) of patients with tumors associated with endometriosis compared to PSC controls were 75% vs. 55% (P = 0.03) and 85% vs. 77% (P = 0.2), respectively.

Conclusions

Patients with tumors associated with endometriosis had a higher rate of synchronous endometrial cancer. Cases also demonstrated a lower rate of recurrence and improved 5 year DFS; however, this did not translate into a difference in OS.     

Demographic and genetic characteristics of patients with borderline ovarian tumors as compared to early stage invasive ovarian cancer

OBJECTIVE: Evaluation whether Jewish founder mutations in BRCA predispose to borderline tumors as they do to early invasive ovarian cancers. METHODS: All Jewish women with borderline or invasive ovarian tumors, diagnosed over a 5-year period (1994-1999), were identified in the frame of a nationwide epidemiological study on ovarian cancer in Israel. Out of a total of 1489 patients, 1269 were interviewed; of them 256 (20.2%) patients were identified with stage I and II invasive epithelial ovarian tumors, and 233 (18.3%) patients were identified with borderline tumors. All patients underwent interviews, and blood or tissue samples from 117 borderline tumors and 161 early stage invasive tumors were analyzed for the presence of the 185delAG and 5382insC BRCA1, and the 6174delT BRCA2 Jewish founder mutations. RESULTS: Patients with borderline tumors were younger at diagnosis, and more frequently of the serous type (P < 0.001) as compared to patients with early stage ovarian cancer. Prevalence of Jewish founder mutations in BRCA1 and BRCA2 was only 4.3% of patients with borderline tumors as compared to 24.2% of patients with early stage ovarian cancer (P = 0.001). CONCLUSIONS: This nationwide study comparing patients with early stage borderline and invasive epithelial tumors of the ovary confirms our previous pilot study that showed a lower incidence of BRCA mutations in patients with borderline tumors. Our results suggest that the genetic predisposition and the molecular mechanisms underlying tumor initiation differ between invasive and borderline tumors of the ovary.     

Use of in vitro method to predict response of human ovarian carcinoma cells to chemotherapeutic agents

In vitro tissue culture and sensitivity tests were carried out on 16 cases of ovarian cancer to select the right anticancer drug(s) on an individual basis. The predictive accuracy of the in vitro drug sensitivity tests were 81.8%. The drug(s) suggested by in vitro tests did not reveal any correlation to the type of ovarian cancer. The drug sensitivity of cells from primary growth was different from that of secondary growth. The in vitro screening test also provided the choice of the next best drug(s), once the tumor had become resistant to a particular drug(s). Thus, the overall prognosis of patients at an advanced stage of malignancy could be improved with the help of in vitro predictive tests.     

Oral contraceptive use, reproductive history, and risk of epithelial ovarian cancer in women with and without endometriosis

OBJECTIVE: Women with endometriosis may be at an increased risk of ovarian cancer. It is not known whether reproductive factors that reduce the risk of ovarian cancer in general also reduce risk in women with endometriosis. We investigated whether the odds ratios for ovarian cancer that were associated with oral contraceptive use, childbearing, hysterectomy, and tubal ligation differ among women with and without endometriosis. STUDY DESIGN: We pooled information on the self-reported history of endometriosis from 4 population-based case-controlled studies of incident epithelial ovarian cancer, comprising 2098 cases and 2953 control subjects. We obtained data on oral contraceptive use, childbearing, breastfeeding, gynecologic surgical procedures, and other reproductive factors on each woman. Multivariable unconditional logistic regression was used to calculate odds ratios and 95% CI for ovarian cancer among women with endometriosis compared with women without endometriosis. Similar methods were used to assess the frequencies of risk factors among women with and without endometriosis. Adjustments were made for age, parity, oral contraceptive use, tubal ligation, family history of ovarian cancer, and study site. RESULTS: Women with endometriosis were at an increased risk of ovarian cancer (odds ratio, 1.32; 95% CI, 1.06-1.65). Using oral contraceptives, bearing children, and having a tubal ligation or hysterectomy were associated with a similar reduction in the odds ratios for ovarian cancer among women with and without endometriosis. In particular, the use of oral contraceptives for >10 years was associated with a substantial reduction in risk among women with endometriosis (odds ratio, 0.21; 95% CI, 0.08-0.58). CONCLUSION: Women with endometriosis are at an increased risk of epithelial ovarian cancer. Long-term oral contraceptive use may provide substantial protection against the disease in this high-risk population.     

Morphological changes of the ovarian surface epithelium in women with ovarian polycystic disease or endometrial carcinoma and a control group

The ovarian surface epithelium and that of related inclusion cysts were studied in 50 women with ovarian polycystic disease and they were compared with our preceding observations performed on women with endometrial carcinoma (n = 50) and on women without any hyperplastic or neoplastic genital tract pathology (n = 50). In 16 women (32%) the ovarian epithelium with normal aspect was found on the surface of the ovary and in inclusion cysts. In the remaining 34 women (68%) surface papillomatosis, hyperplastic and metaplastic changes were present on the ovarian surface and/or in the inclusion cysts. These findings were similar to those observed in the group of women with endometrial adenocarcinoma, while the surface epithelium was often normal in the control group. Our observations confirm the hypothesis of a hormonal influence in the hyperplastic and metaplastic modifications of the ovarian epithelium and in the related common epithelial tumors of the ovary.     

Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma

Objective

The renin–angiotensin system (RAS) influences cardiovascular homeostasis, and Angiotensin II type 1 receptor (AGTR1) is the main effector of RAS, and AGTR2 antagonizes AGTR1. Accumulating evidence supports the role of RAS in the paracrine regulation of tumorigenesis in several cancer types. Although treatment with AGTR1 antagonist (losartan) or AGTR2 agonist (CGP42112A) inhibits tumor progression in several cancer cells, their combined treatment has not been reported.

Methods

In this study, we estimated the expression of AGTR1 and AGTR2 in epithelial ovarian cancer cells and tissues. Then, we evaluated the anti-cancer effects of combined treatment with losartan and/or CGP42112A in ovarian cancer cells and human umbilical vein endothelial cells (HUVEC).

Results

AGTR1 protein was detected in 86% of ovarian cancer tissues, while AGTR2 was not detected in immunohistochemistry. The mRNA expression of AGTR1 obtained from the cancer genome atlas (TCGA) dataset showed that AGTR1 overexpression was correlated with poor survival. Treatment with either losartan or CGP42112A reduced the angiotensin II (Ang II)-mediated cell survival in both ovarian cancer cells and HUVEC. Combined treatment with losartan and CGP42112A synergistically decreased cell survival. As a downstream pathway, phosphorylation of phospholipase C β3 (PLC β3) and expression of vascular endothelial growth factor (VEGF) decreased synergistically in combined treatment.

Conclusion

The results suggest that dual regulation of AGTR1 and AGTR2 may be a novel therapeutic strategy for epithelial ovarian carcinoma through inhibition of cancer cell survival as well as anti-angiogenesis.

Translational relevance

This study investigated the expressions of AGTR1 and AGTR2 in epithelial ovarian carcinoma and the therapeutic potential of AGTR modulation with specific antagonist and/or agonist in epithelial ovarian cancer cells. Treatment of AGTR1 antagonist, losartan and/or AGTR2 agonist, CGP42112A synergistically mediated anti-cancer effects including the decrease of cell survival and down-regulation of VEGF.