BACKGROUND: Inactivation of the retinoblastoma protein (pRb) is a mechanism by which tumor cells can subdue normal growth control. Among the molecules involved in control of pRb phosphorylation, cyclin D1 and cyclin E have been found to be deregulated and overexpressed in various types of cancers. METHODS: Immunohistochemical stains for pRb, p16, cyclin D1 and cyclin E were performed in 73 cases of infiltrating duct carcinomas of the breast. In addition to analysis of their expression rates, the relationships between their expressions and the clinicopathologic parameters were evaluated. RESULTS: pRb, p16, cyclin D1 and cyclin E were positive in 64.7% (44 out of 68 cases), 24.6% (15 out of 61 cases), 43.8% (32 out of 73 cases) and 61.6% (45 out of 73 cases), respectively. Their expression rates were not significantly associated with clinicopathologic prognostic factors. 33 out of 38 cases with p16-negative reactions were pRb positive, while 10 out of 15 cases with pRb-negative reactions were p16 positive. There was a significant inverse relationship between pRb and p16 expressions (P<0.005). 25 out of 32 cases with cyclin E-positive reactions were cyclin D1-positive, and 25 out of 45 cases with cyclin D1-positive reactions were cyclin E-positive. A statistically significant association was observed between cyclin D1 and cyclin E expressions (P<0.05). CONCLUSIONS: The main mechanism during tumorigenesis of breast carcinoma depends on the cyclin D1/p16/pRb pathway, but cyclin E might play a role in the absence of cyclin D1. The inverse correlation between the pRb and p16 expressions may represent one of the important mechanisms in tumorigenesis, as well.
Breast Neoplasms ; Breast* ; Carcinogenesis ; Coloring Agents ; Cyclin D1* ; Cyclin E* ; Cyclins* ; Phosphorylation ; Retinoblastoma ; Retinoblastoma Protein

OBJECTIVE: The aim of this study is to evaluate the role of tumor suppressor genes, p53 and Rb gene, as well as apoptosis in the carcinogenesis of ovarian epithelial tumors. And the value of these factors as prognostic markers to tell the transformation of borderline tumors to overt carcinomas is also studied. METHOD: Thirty cases of ovarian epithelial benign and borderline tumors and invasive carcinoma were used and the expression of the p53 protein and Rb gene protein were evaluated by immunohistochemical method. The apoptosis was evaluated by TUNNEL method. RESULTS: Positive rate of p53 expression in benign, borderline and invasive tumors were 0, 28, and 94 %, respectively. And also, p53 was highly expressed in chemoresistant cases (2/3), in residual tumor (4/5) and in recurred cancer (2/2). Rb protein was partly lost in the borderline tumors, but the rate of Rb protein loss in both borderline tumors and invasive carcinomas were similar. Apoptosis were more active in overt carcinomas than in borderline and benign tumors. In borderline tumors, p53 protein was expressed as 28.6% positivity, and apoptosis was expressed as 28.6% negativity, which showed indirectly that there was apoptosis induction effect of p53. In ten cases of invasive carcinomas showing highly expressed p53, apoptosis revealed all positive reaction except 2 cases, and Rb protein revealed variously. This result supported the apoptosis imduction effect of p53, but it was difficult to find the association of expression degree between the two tumor supressor genes CONCLUSION: In conclusion, the values of p53 is a discriminating factor of malignancy from benign and the expression of p53 is related with clinical aggressivity such as recurrence and residual cancers. Apoptosis are more active in overt carcinoma than in benign & borderline tumor, and in borderline tumor the expression of p53 is related to apoptosis induction which results to carcinomatous change.
Apoptosis* ; Carcinogenesis ; Genes, Retinoblastoma* ; Genes, Tumor Suppressor ; Neoplasm, Residual ; Recurrence ; Retinoblastoma Protein

BACKGROUND: Aberrations of cell cycle-related genes have been reported to contribute to the formation and development of various human tumors. To investigate the gastric carcinogenesis, the expression of cell cycle-related genes (p53, p21wafl/cipl, cyclin D1 and Rb protein) compared to the morphological changes of gastric epithelial lesions were studied. METHODS: The expression of p53, p21wafl/cipl, cyclin D1 and Rb protein was immunohistochemically studied in a series of surgical specimens including the 36 normal/regenerating lesions and the 127 gastric epithelial proliferative lesions (GEPLs). The gastric epithelial proliferative lesions consisted of 25 regenerating epithelia with atypias (REAs), 27 low grade gastric dysplasias (LGDs), 17 high grade dysplasias (HGDs), 24 early gastrc carcinomas (EGCs), and 34 advanced gastric carcinomas (AGCs). RESULTS:The frequency of p53 protein overexpression was significantly associated with histologic grades of GEPLs (p=0.031); occurring in 4% of REAs, in 14.8% of LGDs, in 23.5% of HGDs, in 41.7% of EGCs and 58.9% of AGCs. The p21 wafl/cipl immunohistochemical reaction showed superficial eccentric positivity, representing an inverse correlation with histologic grades of GEPLs (p=0.04); occurring in 83.4% of normal/regenerating lesions, in 80% of REAs, in 74.1% of LGDs, in 29.4% of HGDs, 20.8% of EGCs and 8.8% of AGCs. Although Cyclin D1 and Rb proteins were expressed highly in the GEPLs, the frequency of both proteins were insignificantly associated with histologic grades of GEPLs (p=0.092). However, cases with both the Rb and cyclin D1 positivity were increased with statistical significance along histologic grades of GEPLs (p=0.044). CONCLUSIONS: The altered expression of p53, p21, Rb, and cyclin D1 was considered to be related to dysplastic progression and advancement of malignancy in GEPLs. Therefore, immunohistochemical studies of cell cycle related proteins and a combined analysis may be useful for estimating and following up cases of GEPLs.
Carcinogenesis ; Cell Cycle ; Cyclin D1* ; Cyclins* ; Humans ; Retinoblastoma Protein

PURPOSE: This study was performed to evaluate prognostic significance of Rb and p53 protein immunostaining in renal cell carcinoma. We investigated correlations between Rb, p53 immunostaining and nuclear grade and stage as prognostic factors of renal cell carcinoma. MATERIALS AND METHODS: Subjects of this study were sixty-nine cases of renal cell carcinoma. We used indirect immunohistochemical methods in the formalin-fixed paraffin- embedded tissue (Rb: Pharmingen, USA; p53: Novocastra, UK). In staging and nuclear grading of the renal cell carcinoma, the American Joint Commitee on Cancer (AJCC) TNM system and Fuhrmans grading system were applied respectively. RESULTS: According to Fuhrmans grading system, four cases were classified grade I, 15 cases were classified grade II, 13 cases were classified grade III, and 37 cases were classified grade IV. By AJCC TNM staging system, 29 cases were grouped stage I, 20 cases were grouped stage II, 15 cases were grouped stage III and five cases were grouped stage IV. In 55 cases (79% of all cases), Rb protein was expressed. Expression of Rb protein did not correlate with nuclear grade nor tumor stage. p53 protein was expressed in 17 cases (24% of all cases). p53 protein expression was frequently detected in high nuclear grade group (p < 0.05), but was not correlated with tumor stage. CONCLUSION: Expression of Rb protein was not conelated with nuclear grade and stage. And expression of p53 protein was not correlated with stage, but it is correlated with nuclear grade. Thus immunohistochemical examinstion of p53 could be a histological prognostic factor.
Carcinoma, Renal Cell* ; Joints ; Neoplasm Staging ; Prognosis ; Retinoblastoma Protein

The variety of human cancers in which the retinoblastoma protein pRb is inactivated reflects both its broad importance for tumor suppression and its multitude of cellular functions. Accumulating evidence indicates that pRb contributes to a diversity of cellular functions, including cell proliferation, differentiation, cell death, and genome stability. pRb performs these diverse functions through the formation of large complexes that include E2F transcription factors and chromatin regulators. In this review we will discuss some of the recent advances made in understanding the structure and function of pRb as they relate to tumor suppression, and highlight research using Drosophila melanogaster that reveals important, evolutionarily conserved functions of the RB family.
Animals ; Humans ; Neoplasms ; etiology ; pathology ; prevention & control ; Retinoblastoma Protein ; metabolism

OBJECTIVES: Recently, the studies for oncogene and tumor marker have been actively performed to investigate the carcinogenesis of gastric carcinoma, but it is not clearly understood. We investigated the expression of tumor suppressor gene and proliferation activity in gastric carcinoma. METHODS: Immunohistochemistry for p53 protein (wild and mutant type), retinoblastoma protein(wild type), and PCNA was performed in 131 cases of formalin fixed paraffin embedded tissue sections of gastric carcinoma. We compared that expression with tissue invasiveness, lymph node metastasis, staging and, Lauren classification, and that expression with each other. RESULTS: 1) The positive ratio of p53 protein, Rb protein, also PCNA in gastric carcinoma was 64.9%, 98.5%, 99.2%, 2) The expression of p53 protein was related to invasiveness, lymph node metastasis, staging, and Lauren classification(p<0.05). 3) The positive reaction for Rb gene was identified in tumor cells as well as proliferating cells. 4) There was a close relationship between Rb gene expression and PCNA in gastric carcinoma (p<0.05). CONCLUSION: Theses results suggested that the expression of p53 gene is related to invasiveness, lymph node metastasis, staging and Lauren classification in gastric carcinoma. Expression of retinoblastoma gene is a closely related to proliferating activity.
Carcinogenesis ; Classification ; Dronabinol* ; Formaldehyde ; Genes, p53 ; Genes, Retinoblastoma ; Genes, Tumor Suppressor ; Immunohistochemistry ; Lymph Nodes ; Neoplasm Metastasis ; Oncogenes ; Paraffin ; Proliferating Cell Nuclear Antigen* ; Retinoblastoma ; Retinoblastoma Protein

There is increasing evidence that inactivation of tumor-suppressor genes can promote tumor growth. Retinoblastoma protein (pRb) is the product of the retinoblastoma gene located on chromosome 13q14. pRb negatively regulates cell growth when functioning normally. Mutational inactivation of the Rb gene has been observed in retinoblastomas, osteosarcomas and soft tissue sarcomas. Recently, several other human cancers have also been shown to carry abnormalities of the Rb gene. The potential role of the Rb gene in cutaneous squamous cell carcinomas (SCCs) and basal cell caicinomas (BCCs), has not been determined and was the focus of this study. Immunohistochemical expression of pRb in 16 cutaneous SCCs and 17 BCCs was examined. The expression of PCNA was studied in parallel to assess the cellular proliferation rate in these lesions. The pRb and PCNA immunoreactivity were localized to the nuclei of tumor cells. A few pRb and PCNA positive cells were seen in normal squamous epithelium, sebaceous glands, sweat glands and hair follicles. The loss of expression of pRb was seen in 3 of 16 SCCs(18.8%) and 6 of 17 BCCs (35.3%). PCNA immunoreactivity was slightly high in pRb-negative or lower-positive cases. PCNA immunoreactivity was similar to that produced by pRb in some cases. These results suggest that mutational inactivation of the Rb gene may be related to the carcinogenesis of cutaneous SCC and BCC, though the frequency is relatively low.
Carcinogenesis ; Carcinoma, Basal Cell* ; Carcinoma, Squamous Cell* ; Cell Proliferation ; Epithelium ; Genes, Retinoblastoma ; Hair Follicle ; Humans ; Osteosarcoma ; Proliferating Cell Nuclear Antigen ; Retinoblastoma Protein* ; Retinoblastoma* ; Sarcoma ; Sebaceous Glands ; Sweat Glands

BACKGROUND: Altered cell cycle regulation may underlie the development and/or progression of human malignancies. The purpose of this study is to determine if the oncogenesis of soft tissue sarcomas could be better explained by examining the components involved in G1 phase progression. METHODS: Sixty-seven soft tissue sarcomas were studied for the immunohistochemical expression of cdk4, cyclin D1, retinoblastoma (Rb) and p16 proteins. For Rb and p16, samples showing either negative or heterogeneous (<80% of tumor cells) staining were considered to be altered. RESULTS: The cdk4 protein was observed in 64 cases (95.5%). Cyclin D1 was expressed in 14 cases (20.9%). The Rb expression was altered in 48 (71.6%). Sixty-three (94%) sarcomas demonstrated altered p16 expressions. All of the samples displayed altered expressions of either Rb or p16. A high percentage of the tumors with altered Rb were observed in relapsed patients (p<0.05). CONCLUSIONS: Disturbance in the cell cycle regulatory system involving the Rb/p16/cdk4/cyclin D1 pathway appears to be relatively frequent in soft tissue sarcomas and may play an important role in the tumorigenesis of these tumors. It is noteworthy that the reduced Rb expression correlates with tumor relapse, suggesting its prognostic significance.
Carcinogenesis ; Cell Cycle ; Cyclin D1* ; Cyclin-Dependent Kinase 4 ; Cyclins* ; G1 Phase ; Humans* ; Recurrence ; Retinoblastoma ; Retinoblastoma Protein* ; Sarcoma*

PURPOSE: To investigate the prognostic role of apoptosis and to evaluate the relationship between apoptosis and apoptosis-related genes, as well as cell proliferation in renal cell carcinoma (RCC). MATERIALS AND METHODS: Apoptosis was detected by using the terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick-end labeling (TUNEL) technique in 67 formalin-fixed and paraffin-embedded RCC specimens. Immunohistochemical stainings for p53 and retinoblastoma (Rb) proteins and proliferating cell nuclear antigen (PCNA) were also conducted simultaneously. RESULTS: The apoptotic index (AI) varied from 0.2% to 25.5%. The PCNA index (PI) ranged from 2.1% to 70.3%. The expression of p53 protein was found in 31 of 67 (46.3%) cases. Abnormal expression of Rb was seen in 23 of 67 (34.3%) cases. There was a statistically significant positive correlation between AI and increasingnuclear grade (p<0.001). A significant correlation was found between AI and PI (r=0.329, p<0.01). When comparing the AI with the expression of p53 and Rb proteins, there was no significant difference. In univariate survival analysis, nuclear grade, TNM stage, PI, expression of Rb and AI were significantly associated with shortened survival. However, TNM stage was the only independent prognostic factors by multivariate analysis. CONCLUSION: The present findings indicate that apoptosis in RCC is closely associated with cell proliferation, but not with the expression of p53 and Rb proteins. In multivariate analysis, the AI does not carry an independent prognostic significance.
Apoptosis* ; Carcinoma, Renal Cell* ; Cell Proliferation* ; DNA Nucleotidylexotransferase ; Genes, vif ; Multivariate Analysis ; Proliferating Cell Nuclear Antigen ; Retinoblastoma ; Retinoblastoma Protein

Human papillomavirus type 16 (HPV-16) plays an etiological role in benign and malignant epithelial tumors. A critical event in HPV transformation of human cells is the inactivation of retinoblastoma protein (pRB) by the E7 protein. The metabolic half-life of pRB is decreased in cells that express high-risk HPV E7 proteins. The present study investigated the frequency of HPV-16 E7 variants in Korean women and compared the pRB degradation activity of E7 variant proteins. Of the 40 HPV-positive specimens from a total of 91 tissue specimens, 21 HPV-16 positive specimens were studied by sequencing analysis to determine the variation of E7 gene. The most frequent E7 variant was N29S (57%). The HPV-16 E7 variant was more prevalent in invasive cervical cancer tissue specimens than in those from low grade clinical stage. The degradation of pRB in HaCaT cells by HPV-16 E7 variant proteins was investigated by western blot analysis. There was no significant difference in pRB degradation activity between the HPV-16 E7 prototype protein and E7 variant proteins. The pRB degradation activity did not differ among HPV-16 E7 variants. These results suggest that the E7-induced degradation of pRB is important in cervical tumorigenesis; however, there was no relation between the pRB degradation activity and the variations in HPV-16 E7 protein among Korean women.
Blotting, Western ; Carcinogenesis ; Carcinoma ; Female ; Half-Life ; Human papillomavirus 16 ; Humans* ; Retinoblastoma Protein ; Retinoblastoma* ; Uterine Cervical Neoplasms