GnRH agonist pre-treatment for microwave endometrial ablation in women with less than 1 centimetre myometrial thickness.

We evaluated the efficacy of gonadotropin-releasing hormone agonist (GnRHa) therapy for improving the myometrial thickness in women with thin (less than 1 cm) uterine walls, a contraindication for microwave endometrial ablation (MEA). The normal myometrium thickness was 0.5 cm, 0.7 cm and 0.9 cm. After the third GnRHa dose, the myometrial thickness increased to over 1 cm in all the three patients, and all were able to undergo MEA. The VAS score for menorrhagia improved in all the cases. The patient satisfaction levels were 10 in 2 of the 3 patients, and 5 in the other. There was no symptom recurrence, and no adjuvant therapy was administered. GnRHa therapy in women with submucous leiomyomata and a myometrial thickness of less than 1 cm could effectively thicken the myometrium, allowing for the use of MEA.

Efficacy of multiple microwave endometrial ablation technique for menorrhagia resulting from adenomyosis.

AIM: Conventional microwave endometrial ablation (MEA) can be insufficient to control menorrhagia resulting from adenomyosis. We compared the standard single ablation technique with multiple MEA - repeating ablation three times in the same region - in patients with adenomyosis and menorrhagia. MATERIAL AND METHODS: We performed single MEA in 18 patients and multiple MEA in seven patients between 2007 and 2013. We compared the efficacy of single and multiple MEA using a visual analog scale (VAS) for menorrhagia, dysmenorrhea, and patient satisfaction. We also evaluated the incidence of menorrhagia recurrence, amenorrhea, and procedure complications in relation to patients' clinical factors. RESULTS: VAS scores for improved menorrhagia and patient satisfaction were significantly higher in the multiple MEA group than in the single MEA group; however, the operative time was longer in the multiple-treatment group. There were no statistical differences between groups in hemoglobin levels, VAS improvement for dysmenorrhea, menorrhagia recurrence, frequency of complications, or amenorrhea rate. CONCLUSION: Multiple MEA successfully controls menorrhagia from adenomyosis and achieves a higher satisfaction rate than single MEA.

Microwave endometrial ablation at a frequency of 2.45 GHz for menorrhagia: analysis of treatment results at a single facility.

AIM: We aimed to evaluate the efficacy of microwave endometrial ablation at a frequency of 2.45 GHz in women with menorrhagia. This method has been attracting attention as an alternative to hysterectomy in the treatment of functional and organic menorrhagia. MATERIAL AND METHODS: We performed microwave endometrial ablation in 103 women with menorrhagia between August 2007 and October 2012. All patients had completed child bearing. We evaluated the efficacy of microwave endometrial ablation using a visual analog scale for menorrhagia, dysmenorrhea, and patient satisfaction. We also evaluated the incidence of hypermenorrhea recurrence, amenorrhea, and procedure complications in relation to patients' clinical factors, such as the presence of myoma, adenomyosis, uterine size, and type of bleeding. RESULTS: A total of 76 patients completed the evaluation period. Excessive menstruation improved from a preoperative mean visual analog score of 10, to 1.9 after treatment. Dysmenorrhea improved from a mean score of 4.2, to 1.3, and patient satisfaction had a mean score of 9.0. Hemoglobin levels improved from 10.1 g/dL preoperatively to 12.5 g/dL postoperatively. Four patients experienced recurrence of excessive menstruation. No related clinical factors could be identified for recurrence risk or the occurrence of postoperative infection. A total of 26 patients (34.2%) became amenorrheic; these patients were less likely to have myomata, intramural myomata, and myomata larger than 5 cm. CONCLUSIONS: Microwave endometrial ablation at a frequency of 2.45 GHz is an effective and safe treatment. It should be considered as a standard treatment for conservative therapy-resistant menorrhagia.

Fatty acid synthase is a potential therapeutic target in estrogen receptor-/progesterone receptor-positive endometrioid endometrial cancer.

OBJECTIVE: In the current study we investigated the clinicopathological significance of fatty acid synthase (FASN) expression and its relationship with estrogen receptor (ER) and progesterone receptor (PR) in endometrioid endometrial cancer. METHODS: FASN expression in endometrioid endometrial cancer was assessed by immunohistochemistry using 108 paraffin-embedded tissue specimens and clinical data collected from a retrospective chart review. The specific FASN inhibitor C75 was used to analyze the relationship between FASN expression and cell growth as well as ER/PR expression in endometrioid endometrial cancer cell lines. RESULTS: Positive FASN immunostaining was observed in 77.8% (84/108) of the tumors analyzed. Deep myometrial invasion was significantly and inversely correlated with positive FASN expression (p = 0.024). Positive ER (p = 0.018) and PR status (p = 0.012) was significantly correlated with positive FASN expression. Patients with positive FASN expression in endometrioid endometrial cancer tissues tended to have a favorable progression-free/overall survival (p = 0.127 and p = 0.087, respectively). Ishikawa cells with high FASN expression also showed high expression of ER/PR, while HEC1B cells had low expression levels of both FASN and ER/PR. FASN inhibition by C75 (10 µM) significantly reduced ER/PR expression compared with control dimethyl sulfoxide treatment of Ishikawa cells. The growth of Ishikawa cells having positive FASN and ER/PR expression was significantly inhibited in the presence of C75 or FASN small-interfering RNA compared to HEC1B cells that lacked FASN and ER/PR expression. CONCLUSION: The current findings suggest that there may be cross talk between the ER/PR and FASN signaling pathways that modulate ER/PR activation and could play a role in endometrioid endometrial cancer pathogenesis.

Is ATP7B a predictive marker in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy?

OBJECTIVE: This study examined the prognostic significance of copper-transporting P-type adenosine triphosphatase (ATP7B) expression in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy. METHODS: Expression of ATP7B in ovarian carcinoma was assessed by immunohistochemistry and clinical data collected by retrospective review of medical charts. RESULTS: Overexpression of ATP7B was identified in 25 (29.1%) of 86 ovarian carcinomas. The frequency of ATP7B expression in clear cell carcinomas was significantly higher than that in serous high-grade carcinomas (P < 0.05). We observed no statistically significant correlations between high ATP7B protein expression and either disease-free survival (P = 0.722) or overall survival (P = 0.389). CONCLUSIONS: Our study is the first to demonstrate a lack of statistically significant differences between ATP7B positive and negative cases with respect to prognosis of patients with ovarian carcinoma treated with a platinum-taxane combination regimen. However, that ATP7B expression in clear cell carcinomas was significantly higher than that in serous carcinomas may partially explain the difference in chemotherapeutic response and prognosis between patients with these 2 types of carcinomas.

A Case of Stage III c Ovarian Clear Cell Carcinoma: The Role for Predictive Biomarkers and Targeted Therapies.

Ovarian cancer treatment presently does not reflect molecular differences in histologic subtype. Ovarian clear cell carcinoma (OCCC) exhibits several differences in terms of molecular pathogenesis and tumor behavior from the more common, chemosensitive, serous carcinomas, which makes OCCC a candidate for targeted therapies. A 53-year-old Japanese woman was diagnosed with stage IIIc ovarian clear cell adenocarcinoma with marked chemoresistance to conventional regimens. She demonstrated a partial response to a multikinase inhibitor. The tumor was resistant to PI3K/mTOR pathway inhibitors despite harboring a PIK3CA mutation. The present case suggests a role for targeted therapies in the treatment of OCCC and a need for the identification of biomarkers that will predict response to targeted therapies.

KRAS and MAPK1 gene amplification in type II ovarian carcinomas.

In this study, we examined the clinical significance of KRAS and MAPK1 amplification and assessed whether these amplified genes were potential therapeutic targets in type II ovarian carcinoma. Using fluorescence in situ hybridization, immunohistochemistry, and retrospectively collected clinical data, KRAS and MAPK1 amplifications were identified in 9 (13.2%) and 5 (7.4%) of 68 type II ovarian carcinoma tissue samples, respectively. Interestingly, co-amplification of KRAS and MAPK1 seemed to be absent in the type II ovarian carcinomas tested, except one case. Active phospho-ERK1/2 was identified in 26 (38.2%) out of 68 type II ovarian carcinomas and did not correlate with KRAS or MAPK1 amplification. There was no significant relationship between KRAS amplification and overall or progression-free survival in patients with type II ovarian carcinoma. However, patients with MAPK1 amplification had significantly poorer progression-free survival than patients without MAPK1 amplification. Moreover, type II ovarian carcinoma cells with concomitant KRAS amplification and mutation exhibited dramatic growth reduction following treatment with the MEK inhibitor PD0325901. These findings indicate that KRAS/MAPK1 amplification is critical for the growth of a subset of type II ovarian carcinomas. Additionally, RAS/RAF/MEK/ERK pathway-targeted therapy may benefit selected patients with type II ovarian carcinoma harboring KRAS/MAPK1 amplifications.

Prognostic and therapeutic impact of the chromosome 20q13.2 ZNF217 locus amplification in ovarian clear cell carcinoma.

BACKGROUND: The goal of this study was to examine the clinical significance of ZNF217 amplification and assess whether ZNF217 could be a potential therapeutic target in ovarian clear cell carcinoma (OCCC). METHODS: ZNF217 expression and amplification in OCCC was assessed by immunohistochemistry, fluorescence in situ hybridization, and clinical data collected via a retrospective chart review. ZNF217 gene knockdown using silencing RNA (siRNA) was used to assess ZNF217 functions in OCCC cell lines. RESULTS: Gene amplification was identified in 12 of 60 (20.0%) OCCCs. ZNF217 copy number correlated significantly with ZNF217 protein expression (r = 0.341; P<.01). ZNF217 amplification correlated significantly with shorter progression-free (P = .0042) and overall (P = .0199) survival. There were nonsignificant trends between high ZNF217 protein expression and poor progression-free (P = .2594) and overall (P = .2199) survival. Multivariate analysis revealed ZNF217 gene amplification to be an independent prognostic factor for progression-free and overall survival after standard platinum agent-based chemotherapy (P = .0339 and P = .031, respectively). Profound growth inhibition and apoptosis were observed in ZNF217 siRNA-treated cancer cells with gene amplification compared with cancer cells with ZNF217 moderate expression without ZNF217 gene amplification or with low ZNF217 expression. CONCLUSION: These findings indicate that ZNF217 overexpression is critical to growth and survival of OCCCs with ZNF217 gene amplification. Furthermore, they suggest that ZNF217 siRNA-induced phenotypes depend on amplification status of OCCCs. Therefore, ZNF217-targeted therapy may benefit OCCC patients with ZNF217 amplification.

Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma.

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+) was more frequently found in cells of clear cell carcinomas than in high-grade serous carcinomas (P<0.01). Loss of ARID1A expression was significantly correlated with advanced FIGO stage and high CA125 levels (P=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 (P<0.01). 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=0.03) predictor of reduced progression-free 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=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.

Uterine leiomyosarcoma producing granulocyte colony stimulating factor.

Uterine leiomyosarcoma associated with the paraneoplastic production of granulocyte-colony stimulating factor (GCSF) is extremely rare. No case has been reported to date in the English literature. We describe a case of a 56-year-old female with recurrent uterin leiomyosarcoma, associated with leukocytosis (19100/mm) and an elevated serum GCSF (33.0 pg/ml). Tumore histology was consistent with a well differentiated leiomyosarcoma with marked neutrophilic infiltration of the lung and spleen metastases. tumor cells were distinctly positive for GCSF on immunohistochemistry. These findings confirmed the diagnosis of a GCSF-producting uterine leiomyosarcoma with a paraneoplastic leukocytosis.

Frequent loss of tumor suppressor ARID1A protein expression in adenocarcinomas/adenosquamous carcinomas of the uterine cervix.

OBJECTIVES: Expression of ARID1A (the adenine, thymine-rich interactive domain 1A), a putative tumor suppressor, has recently been shown to be lost in several tumor types. This study investigated whether ARID1A expression was also lost in cervical squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas. METHODS: A total of 91 patients with cervical carcinoma were enrolled. Cervical carcinoma specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, and prognosis were investigated. RESULTS: Using immunohistochemistry, the frequency of loss of ARID1A expression in adenocarcinomas/adenosquamous carcinomas (31.1% [14/45]) was significantly higher than that in squamous cell carcinomas (6.5% [3/46]; P = 0.0017). There was no significant association between the loss of ARID1A expression and International Federation of Gynecology and Obstetrics staging, lymphovascular space invasion, lymph node metastasis, age, and Ki-67 LI in cervical adenocarcinomas/adenosquamous carcinomas. Loss of ARID1A expression was not correlated with shorter overall/disease-free survival in cervical adenocarcinomas/adenosquamous carcinomas. CONCLUSIONS: In conclusion, this study provides the first evidence of the frequent loss of ARID1A protein expression in cervical adenocarcinomas/adenosquamous carcinomas. No significant differences between ARID1A positive and negative cases were observed with respect to any clinicopathological features examined.

Sister Mary Joseph's nodule associated with rare endometrial squamous cell carcinoma.

BACKGROUND: Umbilical metastasis (Sister Mary Joseph's nodule) is a rare physical sign seen only in 1-3 % of patients with an intra-abdominal and/or pelvic malignancy. Here, we present a case of Sister Mary Joseph's (SMJN) nodule originating from a primary squamous cell carcinoma of the endometrium, a rare histological subtype. CASE HISTORY: SMJN was detected in a 30-year-old woman after a preoperative CT scan for a suspected umbilical hernia. Subsequent laparotomy and histopathological examination confirmed endometrial squamous cell carcinoma metastasizing to the umbilical region. CONCLUSION: The SMJN may be the first presenting sign of an intra-abdominal and/or pelvic malignancy and may co-exist with an umbilical hernia. Therefore, malignancy should be considered one of the differentials of an umbilical mass.

[A case of stage IVb cervical carcinoma in which survival was prolonged by two different chemotherapies and CCRT].

Pulmonary metastasis from primary cervical carcinoma is rare, with an incidence of 4.16-7.7%. Chemotherapy is the most common treatment; however, the overall prognosis is poor. This case report describes a complete response to CCRT and TC therapy of cervical carcinoma metastatic to the lung. The patient, a 57-year-old woman, was initially diagnosed with FIGO clinical Stage IVb cervical carcinoma with lung metastasis, after presenting with vaginal bleeding. She had a 90 pack/year smoking history. She was initially treated with systemic chemotherapy(TC therapy: PTX, CBDCA 1 course)followed by concurrent chemoradiotherapy(CCRT)with weekly CDDP2 0mg/m2. She had a complete response of her pelvic disease as well as a decrease in the size of metastatic lesions. Following CCRT, she was scheduled to continue TC therapy, but was only able to complete two courses secondary to a myocardial infarction. A lung biopsy at that time showed no evidence of malignancy, and the patient has remained without any evidence of disease for the past six years.

Loss of MKK4 expression in ovarian cancer: a potential role for the epithelial to mesenchymal transition.

In the current study, we investigated the mechanism relating downregulation of mitogen-activated protein kinase kinase 4 (MKK4) expression to development of ovarian cancer. Over-expression of the MKK4 gene in TOV-21 G cells, a line with homozygous deletion of MKK4, resulted in morphologic changes in which cells growing in a scattered, fibroblast-like pattern formed tightly packed colonies. Based on a wound healing assay and a Matrigel invasion assay, we determined that both motility and invasiveness of MKK4-transfected TOV-21G cells were significantly reduced compared to control vector-transfected cells. To confirm that MKK4 expression related to tumor invasion resulted from an epithelial to mesenchymal transition (EMT)-like morphological change, we used 2 independent but complementary approaches. MKK4 gene knockdown in MDAH 2774 cells over-expressing MKK4 increased invasion activity. Additionally, engineered expression of MKK4 in SKOV3 cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of TOVG-21G. Interestingly, we found that MKK4 upregulation caused downregulation of phosphorylated NF-κB and Twist, as well as upregulation of E-cadherin, in TOVG-21G and SKOV3 cells. Reciprocal results were obtained in MDAH 2774 cells with MKK4 knockdown. Our results suggest that MKK4 downregulation causes increased phosphorylation NF-κB. This promotes Twist over-expression, resulting in E-cadherin downregulation that induces EMT in ovarian cancer.

MKK4 acts as a potential tumor suppressor in ovarian cancer.

Our previous studies indicate that loss of MKK4 expression is associated with the progression of ovarian cancer. However, direct evidence that MKK4 inhibits the malignant phenotype of ovarian cancer cells is limited. In the current study, we investigated the mechanism relating loss of MKK4 expression to the development of ovarian cancer. Using cell growth and anchorage-independent assays, we determined that both the growth and colony-forming ability of MKK4-transfected TOV-21G cells, a line with a homozygous deletion of MKK4, were significantly reduced compared to control vector-transfected cells. Overexpression of the MKK4 gene in TOV-21G cells resulted in reduced proliferative activity and increased apoptosis. To confirm that MKK4 expression related to tumor suppress function, we used two independent but complementary approaches. MKK4 gene knockdown in OVK18#2 and MDAH2774 cells, which overexpressed MKK4, increased proliferation activity. Additionally, the engineered expression of MKK4 in SKOV3 cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of TOV-21G. Similar results were produced in tumor xenografts in nude mice. These results indicated that MKK4 acts as a tumor suppressor and may represent an important therapeutic target for the treatment of ovarian cancer.

Microwave endometrial ablation is a highly efficacious way to emergently control life-threatening uterine hemorrhage.

OBJECTIVE: To asses the effectiveness of microwave endometrial ablation (MEA) using a new curved applicator for the emergent control of uterine hemorrhage. STUDY DESIGN: Seven patients received emergency MEA. Three out of seven patients were treated with MEA as their primary procedure, and four out of seven patients were treated for an intraoperative hemorrhage. RESULTS: In all three patients treated preoperatively, MEA was highly effective and successfully controlled acute uterine hemorrhage. Four out of seven patients were treated with MEA for a hemorrhage following resection of a submucosal myoma or polyp. MEA successfully controlled bleeding in all four patients, thereby preventing them from undergoing hysterectomy. CONCLUSION: Our results suggest that emergency MEA is a promising way to control a life-threatening uterine hemorrhage.

[A case of postoperative rapid brain metastasis originating from stage II a cervical adenosquamous cell carcinoma].

Cerebralmetastases from primary cervical carcinomas are very rare with a repeated incidence of 0. 5-1. 2% in various studies. A 46-year-old woman was initially diagnosed and treated for FIGO clinical stage II a cervical carcinoma. She was two gravid, two para. When 40 years old, she had a right hemicolectomy and chemotherapy, due to colon cancer. Her mother also had colon cancer, cervical cancer, and stomach cancer. She had habitually smoked ten/day for 26 years. First, she went to the outpatient clinic, due to abnormal vaginal bleeding. She had a biopsy of her cervix and was diagnosed with cervical cancer. She underwent a radical hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Pathological diagnosis was adenosquamous cell carcinoma of uterine cervix with extensive LVSI and pelvic lymph node metastasis (right internalil iac LN), myometrial invasion (depth 10 mm), anterior vaginal wall metastasis, but no metastasis of vaginal stump. She came to our hospital for radiotherapy. The woman received concurrent chemoradiotherapy(CCRT)with weekly CDDP 30 mg/m² as adjuvant therapy. Shortly after CCRT, she was diagnosed with multiple metastases to the bone, liver, lung, and brain. She received palliative radiotherapy and eventually died four months after being diagnosed. The extremely rapid progression of this patient's disease is unusual. To our knowledge, this is one of the most aggressive cases of cervical adenosquamous cell carcinoma documented.

Functional and clinicopathological analysis of loss of MKK4 expression in endometrial cancer.

OBJECTIVE: In the current study, we investigated the mechanism relating downregulation of mitogen-activated protein kinase kinase-4 (MKK4) expression to the development of endometrial cancer. METHODS: MKK4 expression in endometrial cancer was assessed by immunohistochemistry using 87 paraffin-embedded tissue specimens, and clinical data was collected via a retrospective chart review. MKK4 gene knockdown using silencing RNA and an MKK4 gene transfection system was used to assess MKK4 function in tissue samples of endometrial cancer. RESULTS: Lower expression of MKK4 immunointensity was observed in 63.2% (55/87) of the analyzed tumors. High-grade endometrioid adenocarcinoma (G2 and G3) (p = 0.024), postmenopausal status (p = 0.018), and patient age (≥ 60) (p = 0.012) were significantly correlated with lower MKK4 expression. Patients with lower MKK4 expression in endometrial cancer tissues tended to have a shorter overall survival (p = 0.197). Using cell growth and anchorage-independent assays, we determined that both the growth and colony-forming ability of MKK4-transfected HEC1B cells, a line with a low endogenous expression of MKK4, were significantly reduced compared to control vector-transfected cells. Overexpression of the MKK4 gene in HEC1B cells resulted in reduced cell migration activity in a simulated wound healing assay. To confirm that MKK4 expression is related to tumor suppressor function, we used 2 independent but complementary approaches. MKK4 gene knockdown in JHEM1 cells, which overexpressed MKK4, increased proliferation activity. Additionally, the engineered expression of MKK4 in Ishikawa cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of HEC1B. Similar results were produced in tumor xenografts in nude mice. CONCLUSION: These results indicate that MKK4 acts as a tumor suppressor, and reduced expression of MKK4 may contribute to the development of endometrial cancer.

Biological role and prognostic significance of NAC1 in ovarian cancer.

OBJECTIVE: This study examined the biological and clinical significance of NAC1 expression in ovarian cancer and assessed whether NAC1 has the potential to be a therapeutic target. METHODS: NAC1 expression and gene amplification were assessed in ovarian cancers by immunohistochemistry, fluorescence in situ hybridization, and clinical data collected by a retrospective chart review. NAC1 gene knockdown using silencing RNA and a NAC1 gene transfection system were used to assess NAC1 function in ovarian cancer tissue samples. RESULTS: The frequency of positive NAC1 expression in serous adenocarcinomas (50.0%:22/44) was significantly higher than that in the other histological subtypes (33.3%: 10/30). NAC1 gene amplification was identified in seven (9.5%) of 74 ovarian carcinomas. Positive NAC1 expression significantly correlated with shorter disease-free and overall survival (P = 0.002, P = 0.0048). A multivariate analysis showed that positive NAC1 expression was an independent prognostic factor for disease-free and overall survival after standard platinum-taxane chemotherapy (P = 0.0027, P = 0.0302). Profound growth inhibition, increased apoptosis, decreased cell proliferation, and decreased cell migration and invasion were observed in silencing RNA-treated cancer cells with NAC1 overexpression compared with cancer cells without NAC1 expression. NAC1 overexpression stimulated proliferation, migration, and invasion in ovarian cancer cell lines KF28 and TOV-21G, which normally lacked NAC1 expression. CONCLUSION: These findings indicate that NAC1 over-expression is critical to the growth and survival of ovarian cancers. Furthermore, they suggest that NAC1 silencing RNA-induced phenotypes depend on the expression status of the targeted cell line. Therefore, NAC1-targeted therapy may benefit ovarian cancer patients with NAC1 expression.

Expression of a BTB/POZ protein, NAC1, is essential for the proliferation of normal cyclic endometrial glandular cells and is up-regulated by estrogen.

PURPOSE: The purpose of this study was to investigate the expression and localization of NAC1, a member of the BTB/POZ gene family in the human cyclic endometrium. EXPERIMENTAL DESIGN: NAC1 expression in normal cyclic endometrium was assessed by immunohistochemistry, and data on clinical variables were collected by retrospective chart review. To elucidate the molecular mechanisms of NAC1 expression in the normal endometrium endometrial carcinoma cell lines (Ishikawa, HHUA; ER+, PR+) and primary cultured normal endometria were tested in a sex steroid induction assay and a NAC1 knockdown assay using siRNA. RESULTS: Expression of NAC1 in glandular cells was significantly higher in the early and mid proliferative phases than in the other menstrual phases. Both NAC1 RNA and protein expression were up-regulated by treatment with 10 nmol/L 17beta-Estradiol (E2) in Ishikawa, HHUA and primary cultured normal endometrial cells. The estrogen receptor antagonist ICI 182,780 significantly attenuated E2-induced NAC1 expression. NAC1 gene knockdown inhibited cell growth and induced apoptosis in Ishikawa, HHUA, and normal endometria, all of which expressed NAC1. Furthermore, NAC1 siRNA significantly abrogated estrogen-driven cellular proliferation in Ishikawa, HHUA, and primary cultured normal endometrial cells, whereas the control siRNA had no effect on cell growth in any of these cells. CONCLUSIONS: These findings suggest that NAC1 is functionally involved in E2-induced cell growth of the normal endometrial glandular cells. Because NAC1 is thought to have oncogenic potential, the current findings may provide new insight into the mechanism of estrogen induced endometrial carcinogenesis.