Although some studies have indicated that endometriosis may increase the risk of developing ovarian cancer, there are no data from epidemiologic studies in Japan. We prospectively analyzed all cases of ovarian endometrioma enrolled in the prefecture-wide Shizuoka Cohort Study on Endometriosis and Ovarian Cancer Programme, which was initiated in 1985. To evaluate the risk of ovarian cancer by time periods subsequent to ovarian endometrioma diagnosis, a cohort of 6,398 women with a clinically documented ovarian endometrioma in Shizuoka between 1985 and 1995 was identified from the Shizuoka Cancer Registry (SCR), with follow-up through 2002. Ovarian cancer incidence among cohort members was ascertained by linkage to the SCR using a unique person-identification number. Standardized incidence ratios (SIR) and their 95% confidence intervals (CI) were computed by a use of prefecture-wide rates of ovarian cancer, adjusted for age and calendar year. During follow-up of up to 17 years of the ovarian endometrioma cohort, 46 incident ovarian cancers were identified, yielding that the ovarian cancer risk was elevated significantly among patients with ovarian endometrioma (SIR = 8.95, 95% CI = 4.12-15.3). The SIR did not increase with increasing follow-up duration. The risk increased with increasing age at ovarian endometrioma diagnosis, with a SIR equal to 13.2 (95% CI = 6.90-20.9) in women above 50 years of age. Our findings for the first time support the hypothesis that ovarian endometrioma increases the subsequent risk of developing ovarian cancer in Shizuoka, Japan.

Ovarian cancer is common in women from developed countries. We designed a prospective randomized controlled trial of ovarian cancer screening to establish an improved strategy for the early detection of cancers. Asymptomatic postmenopausal women were randomly assigned between 1985 and 1999 to either an intervention group (n = 41,688) or a control group (n = 40,799) in a ratio of 1:1, with follow-up of mean 9.2 years, in Shizuoka district, Japan. The original intention was to offer women in the intervention group annual screens by gynecological examination (sequential pelvic ultrasound [US] and serum CA125 test). Women with abnormal US findings and/or raised CA125 values were referred for surgical investigation by a gynecological oncologist. In December 2002, the code was broken and the Shizuoka Cohort Study of Ovarian Cancer Screening and Shizuoka Cancer Registry were searched to determine both malignant and nonmalignant diagnoses. Twenty-seven cancers were detected in the 41,688-screened women. Eight more cancers were diagnosed outside the screening program. Detection rates of ovarian cancer were 0.31 per 1000 at the prevalent screen and 0.38-0.74 per 1000 at subsequent screens; they increased with successive screening rounds. Among the 40,779 control women, 32 women developed ovarian cancer. The proportion of stage I ovarian cancer was higher in the screened group (63%) than in the control group (38%), which did not reach statistical significance (P = 0.2285). This is to our knowledge the first prospective randomized report of the ovarian cancer screening. The rise in the detection of early-stage ovarian cancer in asymptomatic postmenopausal women is not significant, but future decisions on screening policy should be informed by further follow-up from this trial.

Recently, the ARID1A gene has been identified as a novel tumor suppressor in ovarian clear cell carcinoma. The prognostic significance of the loss of ARID1A expression is not known. The current study was designed to evaluate whether ARID1A was a prognostic factor for progression, survival, and chemoresistance in ovarian clear cell carcinoma. A total of 60 patients, who were surgically treated for primary ovarian clear cell adenocarcinoma, were enrolled. Surgical specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, prognosis, and chemosensitivity were investigated. Loss of ARID1A expression was identified in 9 (15.0%) of 60 ovarian clear cell carcinoma samples. Loss of ARID1A staining intensity (0 þ ) was more frequently found in cells of clear cell carcinomas than in high-grade serous carcinomas (Po0.01). Loss of ARID1A expression was significantly correlated with advanced FIGO stage and high CA125 levels (P ¼ 0.02, 0.01). There were no significant correlations between loss of ARID1A expression and patient age, status of residual tumor, Ki-67 labeling index, or the status of endometriosis. Loss of ARID1A correlated with shorter progression-free survival of patients with clear cell carcinomas treated with platinum-based chemotherapy (Po0.01). Loss of ARID1A expression tended to correlate with shorter overall survival in patients with ovarian clear cell carcinomas treated with platinum-based chemotherapy. When data were stratified for the multivariate analysis, only the loss of ARID1A expression remained a significant (P ¼ 0.03) predictor of reduced progressionfree survival. Of the 60 patients with ovarian clear cell carcinomas, 14 patients had measurable residual tumor after primary cytoreductive surgery. Tumors with loss of ARID1A expression were more likely to be chemoresistant than tumors with positive ARID1A expression (100.0 vs 40.0%, P ¼ 0.04). This study demonstrates that loss of ARID1A in ovarian clear cell carcinoma is a negative prognostic factor in patients treated with platinum-based chemotherapy. Measurement of ARID1A expression may be a method to predict resistance to platinum-based chemotherapy in patients with ovarian clear cell carcinoma.

Transmembrane ion transport processes play a key role in the adaptation of cells to hyperosmotic conditions. Previous work has shown that the disruption of a ktrB/ntpJ-like putative Na ؉ /K ؉ transporter gene in the cyanobacterium Synechocystis sp. PCC 6803 confers increased Na ؉ sensitivity, and inhibits HCO 3 ؊ uptake. Here, we report on the mechanistic basis of this effect. Heterologous expression experiments in Escherichia coli show that three Synechocystis genes are required for K ؉ transport activity. They encode an NAD ؉ -binding peripheral membrane protein (ktrA; sll0493), an integral membrane protein, belonging to a superfamily of K ؉ transporters (ktrB; formerly ntpJ; slr1509), and a novel type of ktr gene product, not previously found in Ktr systems (ktrE; slr1508). In E. coli, Synechocystis KtrABEmediated K ؉ uptake occurred with a moderately high affinity (K m of about 60 M), and depended on both Na ؉ and a high membrane potential, but not on ATP. KtrABE neither mediated Na ؉ uptake nor Na ؉ efflux. In Synechocystis sp. PCC 6803, KtrB-mediated K ؉ uptake required Na ؉ and was inhibited by protonophore. A ⌬ktrB strain was sensitive to long term hyperosmotic stress elicited by either NaCl or sorbitol. Hyperosmotic shock led initially to loss of net K ؉ from the cells. The ⌬ktrB cells shocked with sorbitol failed to reaccumulate K ؉ up to its original level. These data indicate that in strain PCC 6803 K ؉ uptake via KtrABE plays a crucial role in the early phase of cell turgor regulation after hyperosmotic shock.

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Experiments on cloned ktrB in the pBAD18 vector showed that V. alginolyticus KtrB alone was still active in E. coli. It mediated Na ؉ -independent, slow, high affinity, and mutation-specific K ؉ uptake as well as K ؉ -independent Na ؉ uptake. These data demonstrate that KtrB contains a selectivity filter for K ؉ ions and that all four conserved p-loop glycine residues are part of this filter. They also indicate that the role of KtrA lies in conferring velocity and ion coupling to the Ktr complex.

Urokinase-type plasminogen activator (uPA) has been implicated in tumor cell invasion and metastasis. We reported previously that transforming growth factor (TGF)-␤1 induces a dose-and time-dependent up-regulation of uPA mRNA and protein in highly invasive human ovarian cancer cell line HRA, leading to invasion. To further elucidate the mechanism of the invasive effect of TGF-␤1, we investigated which signaling pathway transduced by TGF-␤1 is responsible for this effect. Here, we show that 1) nontoxic concentrations of TGF-␤1 activated Src kinase; 2) TGF-␤1 rapidly phosphorylates ERK1/2 and Akt, but not p38; 3) pharmacological Src inhibitor PP2 or antisense (AS) c-Src oligodeoxynucleotide (ODN) treatment reduced TGF-␤1-induced phosphorylation of ERK1/2 and Akt by 85-90% compared with controls; 4) pharmacological inhibition of MAPK by PD98059 abrogated TGF-␤1-mediated Akt stimulation, whereas TGF-␤1-induced ERK1/2 stimulation was not inhibited by PI3K inhibitor LY294002 or AS-PI3K ODN transfection; 5) up-regulation of uPA mRNA in response to TGF-␤1 was almost totally blocked by PP2 and PD98059 and partially (ϳ55%) by LY294002; 6) TGF-␤1-induced uPA mRNA up-regulation was inhibited by treatment with AS ODNs to c-Src or PI3K by 90 or 60%, respectively, compared with control ODN treatment; and 7) blockade of the release of the transcription factor NF-B by pyrrolidinedithiocarbamate reduced the TGF-␤1-induced activation of the uPA gene by ϳ65%. In addition, curcumin, a blocker of the transcriptional factor AP-1, partially (35%) canceled this effect. Taken together, these data support a role for TGF-␤1 activation of two distinct pathways (Src-MAPK-PI3K-NF-B-dependent and Src-MAPK-AP-1-dependent) for TGF-␤1-dependent uPA up-regulation and promotion of invasion.The processes of ovarian cancer dissemination are characterized by altered local proteolysis, cellular proliferation, cell attachment, and invasion, suggesting that the urokinase-type plasminogen activator (uPA) 1 could be involved in the pathogenesis of peritoneal dissemination (1). uPA is a serine protease associated with various pathological conditions including tumor invasion and metastasis (2). One of the factors regulating the metastatic process is considered to be transforming growth factor-␤ (TGF-␤), which is a multifunctional cytokine that elicits numerous cellular effects pertinent to the metastatic process (1). TGF-␤ regulates a wide range of physiological and pathological cellular processes, including cell growth, differentiation, invasion, migration, mesenchymal transition, extracellular matrix synthesis, and cell death in many cell types including ovarian cancer cells (3). Recent data demonstrated that TGF-␤ specifically stimulates up-regulation of uPA mRNA and protein in certain types of neoplastic cells (1). The cellular mechanism(s) of the TGF-␤-induced uPA-dependent tumor invasion and metastasis has been extensively studied. The identity of the signaling pathway(s) involved in the TGF-␤-induced uPA up-regulation (4) remains less known. In a well...

Abstract. Women with hereditary breast and ovarian cancer (HBOC) syndrome represent a unique group who are diagnosed at a younger age and result in an increased lifetime risk for developing breast, ovarian and other cancers. This review integrates recent progress and insights into the molecular basis that underlie the HBOC syndrome. A review of English language literature was performed by searching MEDLINE published between January 1994 and October 2012. Mutations and common sequence variants in the BRCA1 and BRCA2 (BRCA) genes are responsible for the majority of HBOC syndrome. Lifetime cancer risks in BRCA mutation carriers are 60-80% for breast cancer and 20-40% for ovarian cancer. Mutations in BRCA genes cannot account for all cases of HBOC, indicating that the remaining cases can be attributed to the involvement of constitutive epimutations or other cancer susceptibility genes, which include Fanconi anemia (FA) cluster (FANCD2, FANCA and FANCC), mismatch repair (MMR) cluster (MLH1, MSH2, PMS1, PMS2 and MSH6), DNA repair cluster (ATM, ATR and CHK1/2), and tumor suppressor cluster (TP53, SKT11 and PTEN). Sporadic breast cancers with TP53 mutations or epigenetic silencing (hypermethylation), ER-and PgR-negative status, an earlier age of onset and high tumor grade resemble phenotypically BRCA1 mutated cancers termed 'BRCAness', those with no BRCA mutations but with a dysfunction of the DNA repair system. In conclusion, genetic or epigenetic loss-of-function mutations of genes that are known to be involved in the repair of DNA damage may lead to increased risk of developing a broad spectrum of breast and ovarian cancers.