Dataset Information

High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer.

ABSTRACT:

Objective

To investigate the association of tumor glucocorticoid receptor (GR) expression and patient outcome in ovarian cancer.

Methods

GR expression was evaluated by immunohistochemistry using tissue microarrays of specimens from 481 patients with ovarian cancer and 4 patients with benign conditions. Low GR expression was defined as an intensity of 0 or 1+ and high GR as 2+ or 3+ in >1% of tumor cells. Analyses were performed to evaluate the relationship of GR expression with clinical characteristics, progression-free survival (PFS) and overall survival (OS).

Results

GR protein was highly expressed in 133 of 341 (39.0%) tumors from patients who underwent upfront cytoreduction surgery followed by adjuvant chemotherapy. High GR expression was more common in serous tumors (p<0.001), high grade tumors (p<0.001), and advanced stage tumors (p=0.037). Median PFS was significantly decreased in cases with high GR (20.4months) compared to those with low GR (36.0months, HR=1.66, 95% CI 1.29-2.14, p<0.001). GR remained an independent prognostic factor for PFS in multivariate analysis. OS was not associated with GR status.

Conclusions

These data suggest that high GR expression correlates with poor prognosis and support the hypothesis that modulating GR activity in combination with chemotherapy may improve outcomes.

SUBMITTER: Veneris JT

PROVIDER: S-EPMC5955699 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer.

Veneris Jennifer Taylor JT Darcy Kathleen M KM Mhawech-Fauceglia Paulette P Tian Chunqiao C Lengyel Ernst E Lastra Ricardo R RR Pejovic Tanja T Conzen Suzanne D SD Fleming Gini F GF

Gynecologic oncology 20170426 1

<h4>Objective</h4>To investigate the association of tumor glucocorticoid receptor (GR) expression and patient outcome in ovarian cancer.<h4>Methods</h4>GR expression was evaluated by immunohistochemistry using tissue microarrays of specimens from 481 patients with ovarian cancer and 4 patients with benign conditions. Low GR expression was defined as an intensity of 0 or 1+ and high GR as 2+ or 3+ in >1% of tumor cells. Analyses were performed to evaluate the relationship of GR expression with cl ...[more]

PMID: 28456378

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Project description:Epithelial ovarian cancer (EOC) has an innate susceptibility to become chemoresistant. Up to 30% of patients do not respond to conventional chemotherapy [paclitaxel (Taxol®) in combination with carboplatin] and, of those who have an initial response, many patients relapse. Therefore, an understanding of the molecular mechanisms that regulate cellular chemotherapeutic responses in EOC cells has the potential to impact significantly on patient outcome. The mitotic arrest deficiency protein 2 (MAD2), is a centrally important mediator of the cellular response to paclitaxel. MAD2 immunohistochemical analysis was performed on 82 high-grade serous EOC samples. A multivariate Cox regression analysis of nuclear MAD2 IHC intensity adjusting for stage, tumour grade and optimum surgical debulking revealed that low MAD2 IHC staining intensity was significantly associated with reduced progression-free survival (PFS) (p = 0.0003), with a hazard ratio of 4.689. The in vitro analyses of five ovarian cancer cell lines demonstrated that cells with low MAD2 expression were less sensitive to paclitaxel. Furthermore, paclitaxel-induced activation of the spindle assembly checkpoint (SAC) and apoptotic cell death was abrogated in cells transfected with MAD2 siRNA. In silico analysis identified a miR-433 binding domain in the MAD2 3' UTR, which was verified in a series of experiments. Firstly, MAD2 protein expression levels were down-regulated in pre-miR-433 transfected A2780 cells. Secondly, pre-miR-433 suppressed the activity of a reporter construct containing the 3'-UTR of MAD2. Thirdly, blocking miR-433 binding to the MAD2 3' UTR protected MAD2 from miR-433 induced protein down-regulation. Importantly, reduced MAD2 protein expression in pre-miR-433-transfected A2780 cells rendered these cells less sensitive to paclitaxel. In conclusion, loss of MAD2 protein expression results in increased resistance to paclitaxel in EOC cells. Measuring MAD2 IHC staining intensity may predict paclitaxel responses in women presenting with high-grade serous EOC.

Project description:BackgroundOvarian carcinoma is the most lethal gynecologic malignancy because of its late diagnosis, extremely high recurrence rate, and limited curative treatment options. In clinical practice, high-grade serous carcinoma (HGSC) predominates due to its frequency, high aggressiveness, and rapid development of drug resistance. Recent evidence suggests that CXCL12 is an important immunological factor in ovarian cancer progression. Therefore, we investigated the predictive and prognostic significance of the expression of this chemokine in tumor and immune cells in patients with HGSC.MethodsWe studied a cohort of 47 primary high-grade serous ovarian carcinomas and their associated recurrences. A tissue microarray was constructed to evaluate the CXCL12 immunostained tumor tissue. CXCL12 expression was evaluated and statistically analyzed to correlate clinicopathologic data, overall survival, and recurrence-free survival.ResultsA high proportion of CXCL12 + positive immune cells in primary ovarian serous carcinoma correlated significantly with chemosensitivity (p = 0.005), overall survival (p = 0.021), and longer recurrence-free survival (p = 0.038). In recurrent disease, high expression of CXCL12 was also correlated with better overall survival (p = 0.040). Univariate and multivariate analysis revealed that high CXCL12 + tumor-infiltrating immune cells (TICs) (HR 0.99, p = 0.042, HR 0.99, p = 0.023, respectively) and combined CXCL12 + /CD66b + infiltration (HR 0.15, p = 0.001, HR 0.13, p = 0.001, respectively) are independent favorable predictive markers for recurrence-free survival.ConclusionA high density of CXCL12 + TICs predicts a good response to chemotherapy, leading to a better overall survival and a longer recurrence-free interval. Moreover, with concomitant high CXCL12/CD66b TIC density, it is an independent favorable predictor of recurrence-free survival in patients with ovarian carcinoma.

Dataset Information

High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer.

Objective

Methods

Results

Conclusions

Publications

High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer.

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