Immunolocalization of ERK1/2 and p-AKT in normal endometrium, endometrial hyperplasia, and early and advanced stage endometrioid endometrial adenocancer and their prognostic significance in malignant group

Güngördük, Kemal; Ertaş, İbrahim Egemen; Şahbaz, Ahmet; Ozvural, Seyfettin; Sarica, Yagmur; Ozdemir, Aykut; Sayhan, Sevil; Gökçü, Mehmet; Yılmaz, Bülent; Şancı, Muzaffer; İnan, Sevinç; Harma, Mehmet; Yıldırım, Yusuf

doi:10.1016/j.ejogrb.2014.05.040

Cited by 6 publications

(11 citation statements)

References 27 publications

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“…In a recent study, nuclear phosphorylated (p) Ser(167)-ERα was reported to significantly positively correlated with p-MAPK and p-S6K1 and with a significantly shorter relapse-free survival in EEA (25). Another study reported that extracellular signal-regulated kinase (ERK1/2) and p-AKT can be useful in the differential diagnosis of benign vs. malignant endometrial lesions as well as early-vs. advanced-stage EEA (26). Similarly, our results suggest that S6K1 immunopositivity could be used as a predictive test in EEAs and is a promising prognostic indicator of advanced stage and higher grade disease.…”

Section: Discussionsupporting

confidence: 67%

Could S6K1 immunopositivity be used to distinguish early and advanced stages of endometrioid endometrial adenocarcinoma?

Gün

Özdamar

Küçükodacı

et al. 2016

J Turkish German Gynecol Assoc

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Conclusion: S6K1 was positive in the majority of EEAs and malignancies at an advanced stage. Higher grade disease had a significantly higher rate of S6K1 positivity. S6K1 immunopositivity appears to be a promising method to predict poor prognosis in EEA. (J Turk Ger Gynecol Assoc 2016; 17: 163-7) Keywords: Endometrioid endometrial adenocarcinoma, P70 ribosomal protein S6 kinase alpha, PI3 K/AKT/mTOR pathway, prognostic indicator Received: 11 April, 2016 Accepted: 28 June, 2016 Could S6K1 immunopositivity be used to distinguish early and advanced stages of endometrioid endometrial adenocarcinoma?İsmet Pathology, Gülhane Military Medical Academy, Haydarpaşa Training and Research Hospital, İstanbul, Turkey Abstract sues of non-pathologic endometrium, early-stage (IA, Grade 1) and advanced-stage (IA, grade 2-3, and IB, II, III, IV) EEA, using indirect immunohistochemistry. Material and MethodsClinical samples This is a cross-sectional study conducted between January 2003 and December 2011. Ethical approval from the Institutional Review Board was granted before the initiation. Patients who underwent surgery for EEA and in whom diagnosis was made upon pathological examination, were extracted retrospectively from the clinic's patient database. The control group consisted of patients undergoing surgery for non-endometrial benign gynecological diseases. Patients who had received treatment that could potentially affect S6K1 immunostaining, such as chemotherapy, radiotherapy, and hormone replacement therapy (HRT) or oral contraceptive pills, and those with concurrent malignancies, cardiac hypertrophy, and type 2 diabetes and obesity, were excluded from the study. All the specimens were re-evaluated by a single pathologist, and all the pathological diagnoses were confirmed by another pathologist before the study. During these examinations, cases without sufficient tissue samples were excluded. Patients diagnosed as EEA by pathological examination were divided into two subgroups: Group 1; grade 1, stage 1A EEA patients, and, Group 2; grade 2 or 3, stage ≥1A EEA patients. Stages for endometrial cancer were determined according to the clinical criteria established by the International Federation of Gynecology and Obstetrics (FIGO) 2014 (10). Clinical and pathology data from the included patients were recorded.Details of the antibody used and analysis of the immunohistochemistry 4 micron thick cross-sections were taken from suitable paraffin blocks. These cross-sections, in conjunction with positive controls, were incubated for 17 hours at 55 0 C, and, after standard deparaffinization and rehydration processes, were applied. Afterwards, the immunohistochemical staining process was manually performed in accordance with the suggested procedure with a 1/100 dilution of polyclonal Rabbit P70S6K1 (Anti-S6K1 antibody (ab47504), Abcam; Cambridge, MA, USA) primer antibody. HeLa cells were used as positive control materials. Evaluation of the stainingThe immunohistochemical results were evaluated under a microscope independen...

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Section: Discussionsupporting

confidence: 67%

Could S6K1 immunopositivity be used to distinguish early and advanced stages of endometrioid endometrial adenocarcinoma?

Gün

Özdamar

Küçükodacı

et al. 2016

J Turkish German Gynecol Assoc

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“…A number of studies, which evaluated both AKT and ERK in tumors, recorded similar frequencies of expression [81–83]. In various cancers, high expression rates of both AKT and ERK have been documented [84–88].…”

Section: Leptin Biology and Molecules Of Relevant Signal Transductmentioning

confidence: 99%

“…For example, David et al noticed that lung cancer patients with strong phosphorylated AKT (p-AKT) expression were more likely to die early [89]. In a study that analyzed endometrial adenocarcinomas, p-AKT expression was significantly higher in women with positive lymph nodes, and higher expression was significantly associated with poor survival [81]. Jia et al recorded that p-AKT expression correlated with higher histological grade and resistance to chemotherapy in ovarian cancer [90].…”

Section: Leptin Biology and Molecules Of Relevant Signal Transductmentioning

confidence: 99%

The potential role of leptin in tumor invasion and metastasis

Ray

Cleary

2017

Cytokine & Growth Factor Reviews

112

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The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin’s association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin’s potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

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“…51 Activation of AKT1 requires translocation to the plasma membrane followed by phosphorylation of the Thr308 and Ser473 residues: high levels of p-AKT1 are a marker of poor prognosis in endometrial and other cancers. 8,52,53 A large number of inhibitors targeting mTOR and/or PI3K have been tested in early clinical trials in multiple tumor types, however, toxicity issues have complicated their ongoing development and many have not been taken forward into large phase III trials. Several AKT inhibitors are also in development, and initial clinical activity recently reported in several different solid tumor types including breast, lung, and gynaecological tumors carrying the AKT1 c.49G>A (p.Glu17Lys) hotspot mutation.…”

Section: Discussionmentioning

confidence: 99%

A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding

Painter

Kaufmann

O’Mara

et al. 2016

The American Journal of Human Genetics

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A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.

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Immunolocalization of ERK1/2 and p-AKT in normal endometrium, endometrial hyperplasia, and early and advanced stage endometrioid endometrial adenocancer and their prognostic significance in malignant group

Cited by 6 publications

References 27 publications

Could S6K1 immunopositivity be used to distinguish early and advanced stages of endometrioid endometrial adenocarcinoma?

Could S6K1 immunopositivity be used to distinguish early and advanced stages of endometrioid endometrial adenocarcinoma?

The potential role of leptin in tumor invasion and metastasis

A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding

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