cyclin-d1 and Endometrial-Hyperplasia

Cyclin D1 is a regulatory subunit of -Cyclin Dependent Kinases 4 and 6 (CDK4/6) and regulates progression from G1 to S phase of the cell cycle. Dysregulated cyclin D1-CDK4/6 contributes to abnormal cell proliferation and tumor development. Phosphorylation of threonine 286 of cyclin D1 is necessary for ubiquitin-dependent degradation. Non-phosphorylatable cyclin D1 mutants are stabilized and concentrated in the nucleus, contributing to genomic instability and tumor development. Studies investigating the tumor-promoting functions of cyclin D1 mutants have focused on the use of artificial promoters to drive the expression which unfortunately may not accurately reflect tumorigenic functions of mutant cyclin D1 in cancer development. We have generated a conditional knock-in mouse model where cyclin D1T286A is expressed under the control of its endogenous promoter following Cre-dependent excision of a lox-stop-lox sequence. Acute expression of cyclin D1T286A following tamoxifen-inducible Cre recombinase triggers inflammation, lymphocyte abnormality and ultimately mesenteric tumors in the intestine. Tissue-specific expression of cyclin D1T286A in the uterus and endometrium cooperates with Pten loss to drive endometrial hyperplasia and cancer. Mechanistically, cyclin D1T286A mutant activates NF-κB signaling, augments inflammation, and contributes to tumor development. These results indicate that mutation of cyclin D1 at threonine 286 has a critical role in regulating inflammation and tumor development.

Topics: Animals; Carcinoma; Cyclin D1; Cyclin-Dependent Kinase 4; Endometrial Hyperplasia; Female; Humans; Inflammation; Mice; PTEN Phosphohydrolase; Threonine

To determine the expression of cyclin D1 and PTEN (phosphatase and tensin homolog) in endometrial hyperplasias and neoplasias.. Analytical study.. The study was conducted at BMSI, JPMC, Karachi, from January 2008 to December 2012.. Analysis of endometrial samples, comprising of hysterectomies and curettage, was carried out. Immunohistochemical staining was done for PTEN and cyclin D1 expression.. Fifty-three endometrial samples including 23 endometrial carcinomas, 6 complex hyperplasias with atypia, 14 complex hyperplasias without atypia, 6 simple hyperplasias without atypia and 4 normal proliferative endometrium were analyzed. Fifty-two percent (12 out of 23) and 48% (11 out of 23) cases of endometrial carcinomas showed complete loss of PTEN expression and cyclin D1 over expression, respectively. Five (5 out of 6) cases of complex hyperplasias with atypia and 64.28% (9 out of 14) cases of complex hyperplasia without atypia showed complete loss of or diminished expression of PTEN whereas 66.66% (4 out of 6) cases of endometrial hyperplasia with atypia and 50% (7 out of 14) cases of endometrial hyperplasia without atypia showed cyclin D1 overexpression (p < 0.001).. Loss of PTEN, expression and cyclin D1 overexpression was seen in a significant number of well differentiated endometrial adenocarcinomas and complex hyperplasias with atypia, suggesting both as an early event in endometrial carcinogenesis.

Topics: Biomarkers, Tumor; Cyclin D1; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Immunohistochemistry; Precancerous Conditions; PTEN Phosphohydrolase

MicroRNAs (miRNAs) are post-transcriptional inhibitor regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for the tumor-suppressor miRNA miR-503 in endometrioid endometrial cancer (EEC) cells. The miR-503 expression level gradually decreases across normal endometrial tissues, endometrial tissues with complex atypical hyperplasia, and EEC tissues. A relatively high level of miR-503 in EEC tissues indicates a longer survival time in EEC patients. The expression of a cell cycle-associated oncogene encoding cyclin D1 (CCND1) was inversely correlated with miR-503 expression in EEC tissues and cell lines. CCND1 has a binding sequence of miR-503 within its 3' untranslated region, and was confirmed to be a direct target of miR-503 by the fluorescent reporter assays. Increasing the miR-503 level in EEC cells suppressed cell viability, colon formation activity and cell-cycle progression, and the inhibited oncogenic phenotypes induced by miR-503 were alleviated by ectopic expression of CCND1 without the untranslated region sequence. Furthermore, in vivo studies also suggested a suppressive effect of miR-503 on EEC cell-derived xenografts. miR-503 increased in cell cycle-arrested EEC cells, and was restored to a normal level in EEC cells after cell cycle re-entry, while CCND1 displayed the opposite expression pattern. Collectively, this study suggested that miR-503 plays a tumor-suppressor role by targeting CCND1. Abnormal suppression of miR-503 leads to an increase in the CCND1 level, which may promote carcinogenesis and progression of EEC.

Topics: 3' Untranslated Regions; Aged; Animals; Carcinoma, Endometrioid; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Gene Expression Regulation, Neoplastic; Gene Transfer Techniques; Genes, Reporter; Humans; Mice; Mice, Nude; MicroRNAs; Middle Aged; Recombinant Proteins; Xenograft Model Antitumor Assays

Alteration of CyclinD1 was suggested to relate with development of endometrial carcinogenesis before, however CyclinD1 expression is not well defined in endometrial hyperplasia lesions. We checked the relationship between its expression and clinic-pathological variables of endometrial lesions to explore the possibility for CyclinD1 as a potential diagnostic and prognostic marker.. Cyclin D1 immunohistochemical analysis (IHC) was used to evaluate 201 fixed, paraffin-embedded endometrial samples which included simple hyperplasia (n = 27), atypical complex hyperplasia (ACH) (n = 41), endometrioid carcinoma (n = 103), endometrial serous carcinoma (ESC) (n = 21) and clear cell carcinoma (CCC) (n = 9). A breast cancer with known CyclinD1 expression was selected as a positive control in each immunohistochemistry run. We also performed follow-up study to estimate patients' prognosis.. CyclinD1 was significantly overexpressed in atypical complex hyperplasia (ACH), endometrioid carcinoma and clear cell carcinoma (CCC). The positive signaling of CyclinD1 was showed less than 40% in simple hyperplasia and endometrial serous carcinoma (ESC). The high expression of CyclinD1 was observed in metastasis carcinoma group more significantly than non-metastasis carcinoma group. Kaplan Meier analysis demonstrated that patients with high CyclinD1 expression had an obviously poor prognosis than patients without CyclinD1 staining (p < 0.05). Moreover, according to multivariate Cox regression analysis, CyclinD1 expression, as crucial as metastasis, was a risk marker for overall survival rate.. CyclinD1 exhibited a promising potential to predict the prognosis of patients with endometrial carcinoma. However, the statistical analysis demonstrated that CyclinD1 exhibited a poor ability to differentiate neoplastic lesions from non-neoplastic lesions; thus, the application of CyclinD1 only is not so credible for differentiation between benign and malignant lesions.. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1871063048950173.

Topics: Adenocarcinoma, Clear Cell; Adult; Biomarkers, Tumor; Biopsy; Carcinoma, Endometrioid; Chi-Square Distribution; Cyclin D1; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Middle Aged; Multivariate Analysis; Neoplasms, Cystic, Mucinous, and Serous; Prognosis; Proportional Hazards Models; Risk Factors; Time Factors; Up-Regulation

Numerous studies support the role for mutations in the phosphatase and tensin homologue (PTEN) tumor suppressor gene and unopposed estrogen stimulation in the pathogenesis of uterine endometrioid carcinoma. However, the relation between PTEN signaling and estrogen/estrogen receptor in endometrial tumorigenesis remains unresolved. We used genetically engineered mice as a model to address this relation. Mice with a single deleted Pten allele (Pten(+/-)) spontaneously develop complex atypical hyperplasia and ~20% develop endometrial cancer. To determine the effect of removing endogenous estrogen, we performed oophorectomies on Pten(+/-) mice. Although there was a reduction in the number and severity of hyperplastic lesions, the endometrial phenotype persisted, suggesting that Pten mutation, independent of estrogen, can initiate the development of complex atypical hyperplasia. To recapitulate the situation in women with unopposed estrogen, we implanted 17β-estradiol pellets in adult female Pten heterozygous mice, resulting in increased carcinoma incidence. Because studies have shown that estrogen largely acts on the endometrium via estrogen receptor ERα, we generated Pten(+/-)ERα(-/-) mice. Strikingly, 88.9% of Pten(+/-)ERα(-/-) mice developed endometrial hyperplasia/carcinoma. Furthermore, Pten(+/-)ERα(-/-) mice showed a higher incidence of in situ and invasive carcinoma, suggesting that endometrial tumorigenesis can progress in the absence of ERα. Thus, the relation between Pten alterations and estrogen signaling in the development of endometrial carcinoma is complex; the results presented herein have important implications for the treatment of endometrial hyperplasia and carcinoma in women.

Topics: Animals; Cell Transformation, Neoplastic; Cyclin D1; Disease Progression; Endometrial Hyperplasia; Endometrial Neoplasms; Estradiol; Estrogen Receptor alpha; Estrogens; Female; Gene Deletion; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Mice; Mice, Transgenic; Neoplasm Invasiveness; Ovariectomy; Precancerous Conditions; PTEN Phosphohydrolase; Signal Transduction

In our research we investigated immunohistochemical expression of cell cycle proteins protein p21, cyclin D1 and cyclin E in physiological endometrium (n = 15), hyperplastic endometrium (n = 61), and post hormone replacement therapy endometrium (n = 24).. We performed immunohistochemical analysis of selected cell cycle proteins in 100 specimens of human endometrium.. The average immunoexpression index scores in glandular endometrial cells (GES) and stromal endometrial cells (SEC) were respectively: for p21- GES: 11.8 +/- 17.19%; SEC: 9.31 +/- 17.15%; for cyclin D1- GES: 9.25 +/- 18.41%; SEC: 3.22 +/- 11.46%; for cyclin E: GES: 26.42 +/- 27.47%; SEC: 4.61 +/- 7.90%. Statistical analysis disclosed more intense p21 glandular immunoreactivity among women with endometrial hyperplasia in comparison to other subpopulations. In the case of assessment of cyclin D1 immunoreactivity, there was no statistical correlation between analysed parameters. The average cyclin E immunoreactivity in endometrial glandular cells was significantly higher (p = 0.003) in women with endometrial hyperplasia and correlated with age.. Intensive immunoreactivity of cyclin E in glandular cells is typical for endometrial hyperplasia and can be treated as an objective indicator of this pathological process during histopathological diagnostic procedures. Immunoreactivity index of p21 and cyclin D1 is independent of the morphological pattern of human endometrium, patients' age and gynaecological history of patients.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Cell Proliferation; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; Endometrial Hyperplasia; Endometrium; Female; Hormone Replacement Therapy; Humans; Immunohistochemistry; Middle Aged; Retrospective Studies; Sensitivity and Specificity

The objective of this study was to investigate the pattern of expression and the localization of Notch-1, Notch-4 and Jagged-1 in physiological and pathological human endometrium and to evaluate the expression levels of two major regulators of the G1 checkpoint, namely cyclin D1 and p21. Sixty samples of physiological endometrium and 60 samples of pathological endometrium were used for the study. Evaluation of the expression level and the distribution of Notch pathway members and cell-cycle proteins was performed by immunohistochemistry. In the physiological endometrium we observed an increase of Notch-1 and Jagged-1 from proliferative to secretory phase and an opposite trend for Notch-4. In menopause, the level of expression of all three members of the Notch pathway decreased. We also observed a cyclin D1 increase from proliferative to secretory phase. By contrast, p21 showed a slight increase from proliferative to secretory phase. In the pathological endometrium, we observed an increase of Notch-1 expression from polyps to carcinoma and decrease for Notch-4 and Jagged-1. Moreover, we observed a higher expression of cyclin D1 in all the endometrial pathologies. By contrast, the expression level of p21 slightly increased from polyps to carcinoma. We concluded that in human endometrium Notch-4 seems to be more involved in controlling proliferation, whereas Notch-1 seems to be more involved in differentiation programming. Deregulation of these functions may induce the onset of several endometrial pathologies from polyps to cancer.

Topics: Analysis of Variance; Biomarkers; Calcium-Binding Proteins; Carcinoma; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Gene Expression; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Menopause; Menstrual Cycle; Proto-Oncogene Proteins; Receptor, Notch1; Receptor, Notch4; Receptors, Notch; Serrate-Jagged Proteins; Signal Transduction

This study investigates the role of cyclin D1 in 30 uterine surgical resection and endometrial biopsy specimens from 30 patients with simple hyperplasia (10 cases), complex hyperplasia (6 cases) and endometrial carcinoma (14 cases). Cyclin D1 immunohistochemistry was performed on 2-4 mm thick paraffin sections using labelled streptavidin biotin kit. Cyclin D1 expression was present in 2/6 (33%) cases of complex hyperplasia, 7/14 (50%) cases of endometrial carcinoma and none in simple hyperplasia. Difference in cyclin D1 immunopositivity in simple hyperplasia and endometrial carcinoma was statistically significant (p = 0.018) but the difference in cyclin D1 immunopositivity between complex hyperplasia and endometrial carcinoma was not statistically significant. Our study suggests that cyclin D1 over-expression may be an early event in endometrial carcinogensis. Since there was no difference in extent and intensity of cyclin D1 expression between complex hyperplasia and endometrial carcinoma, it appears that deregulation is maximal in complex hyperplasia.

Topics: Cyclin D1; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Immunohistochemistry

We investigated cyclin D1 expression in proliferative endometrium, endometrial hyperplasia and endometrioid adenocarcinoma, and examined the correlation of cyclin D1 expression with Ki67 as a cell proliferation associated marker. Immunohistochemical expression of cyclin D1 and Ki67 were studied in 30 cases with endometrial carcinoma, 14 cases with atypical hyperplasia, 15 cases with simple hyperplasia and 30 cases with proliferative endometrium.. One out of 30 patients (3.3%) with proliferative endometrium, 1 out of 14 patients (7.1%) with atypical hyperplasia, and 8 out of 30 patients (26.6%) with endometrial carcinoma were found to have immunoreactivity to cyclin D1. All cases of simple hyperplasia had negative staining for cyclin D1. A positive immunoreaction for Ki67 was obtained in all cases. Statistically significant difference was found in cyclin D1 immunoreactivity between both proliferative endometrium and adenocarcinoma, and simple hyperplasia and adenocarcinoma (p<0.05). In patients with adenocarcinoma, cyclin D1 immunoreactive cases had higher mean Ki67 values compared with the non-immunoreactive ones (p<0.05). Ki67 and cyclin D1 immunoreactivity had no impact on overall survival. Univariate analysis revealed a significant relationship between survival and grade and stage (p<0.01). Cyclin D1 expression was not correlated with age, depth of myometrial invasion, lymphovascular space involvement, grade, lymph node metastasis and stage.. Cyclin D1 expression in endometrial carcinoma is higher than proliferative endometrium and simple hyperplasia. These findings support that cyclin D1 may play a role in endometrial carcinogenesis.

Topics: Biomarkers; Carcinoma, Endometrioid; Cell Proliferation; Cyclin D1; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Ki-67 Antigen; Middle Aged

PTEN is a tumor suppressor gene that inhibits cell proliferation by regulating intracellular signaling pathways, and this activity can be abolished by mutations of the PTEN gene. This study was designed to examine the correlation of PTEN expression with the expression of cell cycle regulators and with clinicopathological parameters in endometrioid adenocarcinoma of the uterine corpus.. Tissue samples of 117 endometrioid adenocarcinomas in addition to those of 19 normal endometria and 20 endometrial hyperplasias were used for the study. Immunohistochemical staining for PTEN protein was performed with the labeled streptavidin-biotin method on formalin-fixed and paraffin-embedded tissue samples. PTEN expression was represented as the staining score.. Immunohistochemistry showed that the nuclei of cells were positive for PTEN. The PTEN staining score of normal endometrium was significantly higher in the proliferative phase than in the secretory phase. The scores of various endometrial hyperplasias were not significantly different from each other, regardless of the type of hyperplasia. The PTEN staining scores of endometrioid adenocarcinomas were 7.6+/-5.2 in G1, 9.6+/-5.2 in G2, and 11.9+/-3.7 in G3, and increased significantly as the histological grade increased. PTEN staining score was not significantly correlated with clinicopathological parameters such as FIGO stage, myometrial invasion, lymph-vascular space invasion (LVSI), lymph node metastasis or group, but was significantly correlated with labeling indices (LIs) of cell cycle regulators such as Ki-67, cdk2, cyclin A, cyclin D1, cyclin E, p27, and p53. The PTEN staining score of p53-wild cases was significantly lower than that of p53-mutant ones, but there was no significant difference of the score in cases with different PTEN gene status. PTEN expression was significantly lower in cases with both high levels of estrogen receptor and progesterone receptor.. PTEN protein expression was decreased in well-differentiated and less growth-aggressive endometrial carcinoma with wild-type p53 gene and high levels of ER and PR. This suggests that disturbed PTEN expression occurs in an early phase of the tumorigenesis of well-differentiated endometrial carcinoma.

Topics: Adenocarcinoma; Biomarkers, Tumor; Carcinoma, Endometrioid; CDC2-CDC28 Kinases; Cell Cycle Proteins; Cell Differentiation; Cyclin A; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p27; Endometrial Hyperplasia; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Ki-67 Antigen; Lymph Nodes; Lymphatic Metastasis; Neoplasm Invasiveness; Neoplasm Staging; Phosphoric Monoester Hydrolases; PTEN Phosphohydrolase; Receptors, Estrogen; Receptors, Progesterone; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Uterine Neoplasms

The aims of this study were to identity the roles of tumor vessels and hormone receptor status in normal, hyperplastic, and neoplastic endometrium, and to explore their relationships with other prognostic factors of endometrial adenocarcinoma. Endometrial curettage specimens of proliferative phase and secretory phase endometrium, simple hyperplasia with or without atypia, complex hyperplasia with or without atypia, and grade 1 adenocarcinoma were examined for estrogen receptor alpha (ER alpha), progesterone receptor (PgR), Ki-67 labeling index (LI), cyclin D1, microvessel density (MVD), and area of venules (AV) using an immunoperoxidase method. The results showed high levels of ER alpha in complex hyperplasia, and high levels of PgR in simple hyperplasia without atypia. Expression of ER alpha in the endometrium decreased in a stepwise manner from complex hyperplasia without atypia to grade 1 adenocarcinoma. Expression of PgR in the endometrium decreased in a stepwise manner from simple hyperplasia without atypia to grade 1 adenocarcinoma. In contrast, the expressions of Ki-67 LI, cyclin D1, MVD and AV in the endometrium increased in a stepwise manner from normal, simple or complex hyperplasia with or without atypia to grade 1 adenocarcinoma. These changes may become irreversible on progression from simple or complex hyperplasia to neoplasia.

Topics: Adenocarcinoma; Adult; Biomarkers, Tumor; Cyclin D1; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Image Processing, Computer-Assisted; Ki-67 Antigen; Microcirculation; Middle Aged; Neovascularization, Pathologic; Neovascularization, Physiologic; Receptors, Estrogen; Receptors, Progesterone

To investigate episialin/MUC1 expression in the normal, hyperplastic and neoplastic endometrium, and relate patterns of tumour MUC1 reactivity with histopathological characteristics, oestrogen and progesterone receptor (ER and PR) status, bcl-2 and p53 oncoproteins and with clinical behaviour.. We studied 42 normally cycling endometria, 45 endometrial hyperplasias of various forms, and 111 endometrial carcinomas of endometrioid and non-endometrioid cell types with specific monoclonal antibodies employing standard immunohistochemical techniques. The follow-up period ranged from 34 to 182 months with a median of 86 months. Epithelial mucin episialin/MUC1 was consistently expressed in the normal endometrium, following a cyclical pattern: "apical membrane staining" in early and mid-proliferative endometrium; "purely cytoplasmic staining" in late proliferative endometrium; and "cytoplasmic staining with intraluminal secretions" in secretory endometrium. Immunostaining patterns in simple and complex hyperplasia were similar to late proliferative endometrium, while atypical hyperplasias and endometrial carcinomas either simulated patterns of proliferative endometrium or lacked MUC1 reactivity. Membranous MUC1 positivity was statistically more frequent in endometrioid carcinomas compared with carcinomas of non-endometrioid type (P = 0.006). Cytoplasmic MUC1 positivity was significantly associated with poor prognosis, while MUC1-negative carcinomas were associated with PR expression and an improved survival (P=0.04). There was no association of MUC1 patterns with bcl-2 and p53 immunoreactivity or with other histopathological variables.. Episialin/MUC1 is an integral component of the normal premenopausal endometrium and is probably hormonally regulated. It is frequently expressed in endometrial hyperplasias and carcinomas. The loss of MUC1 expression from endometrial carcinomas is associated with a favourable prognosis.

Topics: Adenocarcinoma; Adult; Biomarkers, Tumor; Cyclin D1; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Mucin-1; Neoplasm Staging; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Survival Analysis; Survival Rate; Tumor Suppressor Protein p53

In the normal cell cycle, tumor suppressor gene products (p53) and cyclin (cyclin D1) cooperate. Abnormalities in the cooperation of these factors may result in malignant transformation of the cell. Mutant p53 protein overexpression is defined in many human cancers, including endometrial carcinoma. This study investigated the role of cyclin D1 in the development of human uterine endometrial carcinoma.. Seventy-four patients whose pathology slides contained either normal or hyperplastic endometrium adjacent to endometrial carcinoma were studied. Immunohistochemical staining of the serial paraffin sections was performed using antibodies to p53 and cyclin D1.. The expression of cyclin D1 was restricted to only a few cells of normal and hyperplastic endometrium, whereas it was preferentially expressed in 40% (30/74) of endometrial carcinomas. The cells that overexpressed cyclin D1 also overexpressed p53. Moreover, all 30 cases with varied distributions of cyclin D1-positive cells corresponded identically with the distribution of p53-positive cells. Diffuse positivity for cyclin D1 was specifically observed in clinically advanced stages of pathologic G2 and G3 tumors.. The data suggest that coabnormal expression of cyclin D1 and p53 protein may contribute to the development of endometrial carcinoma and may also be involved in the progression to malignancy.

Topics: Adult; Aged; Carcinoma; Cell Cycle; Cell Transformation, Neoplastic; Coloring Agents; Cyclin D1; Cyclins; Disease Progression; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Middle Aged; Mutation; Neoplasm Staging; Oncogene Proteins; Tumor Suppressor Protein p53