The prognostic impact of some cell cycle regulatory proteins in Egyptian breast cancer patients (original) (raw)
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Cell cycle proteins do not predict outcome in grade I infiltrating ductal carcinoma of the breast
… journal of cancer, 2000
Infiltrating ductal mammary carcinomas are histologically graded according to their extent of differentiation. Welldifferentiated, grade I, tumours have low proliferative activity, usually form tubules and exhibit little nuclear pleomorphism. Despite an apparently reassuring morphology, 10 -15% of grade I ductal carcinomas metastasise, albeit after a prolonged period. Recent evidence supports the view that evolution to higher grade malignancies occurs rarely and that grade I tumours are biologically distinct from grade III tumours. We have examined a series of 148 grade I ductal carcinomas in order to ascertain whether information about the level of expression of cyclin D1, p27, p53, oestrogen receptor status (ER) or proliferative activity could be used to identify those patients with a poor outcome. The majority of tumours expressed high levels of cyclin D1, p27 and ER, low levels of p53 and had low Ki-67 expression and mitotic counts. Cyclin D1, p27 and ER expression were all significantly correlated with each other but not with p53 (cyclin D1 correlation with ER, p ؍ 0.01; cyclin D1 correlation with p27 and ER correlation with p27 both p < 0.0001). Cyclin D1 and ER were also both correlated with Ki-67 (p ؍ 0.01 and p < 0.0001) but not with mitotic count. Our results suggest that cyclin D1, ER and p27 are all markers of well-differentiated tumours and that their detection is related to proliferative activity in a manner reflecting their functional role within the normal cell cycle. However, none of the proteins or markers of proliferative activity were sensitive enough to predict which patients were likely to have a poor outcome.
Pathology & Oncology Research
We aimed to analyze the expression of cell-cycle regulation markersminichromosome maintenance protein 2 (MCM2), Ki-67, Cyclin-A and phosphohistone-H3 (PHH3) − in pre-treatment core-biopsy samples of breast carcinomas in correlation with known predictive and prognostic factors. Totally 52 core biopsy samples obtained prior to neoadjuvant therapy were analyzed. Immunohistochemistry was performed to analyze the expression of MCM2, Ki-67, Cyclin A and PHH3, which were correlated with the following clinicopathological parameters: clinical TNM, tumor grade, biological subtype, the presence of tumor infiltrating lymphocytes (TIL), pathological tumor response rate to the neoadjuvant therapy and patient survival. All investigated markers showed higher expression in high grade and in triple negative tumors (p < 0.01 and p < 0.05, respectively). Hormone receptor negative tumors showed significantly higher expression of Ki-67 (p < 0.01), MCM2 (p < 0.01) and Cyclin A (p < 0.01) than hormone receptor positive ones. Tumors with increased TIL showed significantly higher Ki-67 expression (p = 0.04). Pattern analysis suggested that novel cell-cycle marker-based subgrouping reveals predictive and prognostic potential. Tumors with high MCM2, Cyclin A or PHH3 expression showed significantly higher rate of pathological complete remission. Tumors with early relapse (progression-free survival ≤2 years) and shortened overall survival also show a higher rate of proliferation. Our cell cycle marker (Ki-67, MCM2, Cyclin A, PHH3) based testing could identify tumors with worse prognosis, but with a favorable response to primary systemic therapy. The pattern of cell-cycle activity could also be useful for predicting early relapse, but our findings need to be further substantiated in larger patient cohorts.
Pathology, 2005
Aim: The biological impact of cell cycle regulatory proteins on breast cancer progression is widely recognised, although mostly unclear. The aim of this preliminary study was to investigate the correlations of several cell cycle modulators (p53, p21, pRb, and mdm2) and c-erbB-2 expression with cell proliferation markers (S-phase fraction [SPF] and Ki-67) and overall survival in breast cancer. Methods: The series comprised 50 women with stage I-II invasive ductal breast carcinoma (median follow-up 87 months), who were selected for their tumour proliferative characteristics (15 low, 15 high, and 20 intermediate proliferative tumours). Tumour differentiation was assessed following the Nottingham grading criteria. Cell cycle regulators, oestrogen receptor status, and Ki-67 index were analysed by immunohistochemistry on paraffin embedded material (cut-offs 10%). c-erbB-2 was evaluated according to a standardised immunohistochemical assay and borderline cases were confirmed by FISH analysis. Ploidy and SPF were determined by DNA flow cytometry on frozen samples. Chi-square test and Fisher's exact test were applied to analyse the statistical significance of data. Results: Positive immunostaining was observed in nine (18%) p53+, 30 (60%) p21+, 13 (26%) pRb+, and one (2%) mdm2+ cases. c-erbB-2 expression was considered positive in 11 (22%) cases. In the subset of patients dead of the disease, a high incidence of c-erbB-2 over-expression (7/10, 70%) was verified. In general, no significant correlations among cell cycle regulators or between the latter and histopathological or proliferative characteristics were found. Only the p53-/p21+ phenotype significantly correlated with low SPF (p50.048), and p21 positivity showed a trend to be associated with low SPF (p50.083). No statistically significant correlations between cell cycle inhibitors and clinical outcome were found. On the contrary, c-erbB-2 overexpression showed significant correlations with DNA aneuploidy (p,0.001), high SPF (p,0.001), high tumour grading (p50.008), lack of oestrogen receptors (p50.036), and poor overall survival (p,0.001). Conclusions: The results seem to indicate the lack of correlations of cell cycle regulatory proteins with cell proliferation markers and overall survival in breast cancer, in contrast to c-erbB-2 over-expression which was found to be associated with increased proliferation rate and worse prognosis.
2006
Background: Hyperplasia of usual type (HUT) is a common proliferative lesion associated with a slight elevated risk for subsequent development of breast cancer. Cell cycle-related proteins would be helpful to determine the putative role of these markers in the process of mammary carcinogenesis. The aim of this study was to analyze the expression of cell cycle related proteins in HUT of breast specimens of patients with and without breast cancer, and compare this expression with areas of invasive carcinomas. Results: Immunohistochemical evaluation was performed using antibodies against cell cycle related proteins ER, PR, p53, p21, p63, and Ki-67 in hyperplasia of usual type (HUT) in specimens of aesthetic reduction mammaplasty (ARM), in specimens of mammaplasty contralateral to breast cancer (MCC), and in specimens of invasive mammary carcinomas (IMC) presenting HUT in the adjacent parenchyma. The results showed that the immunoexpression of ER, PR, p21, p53, p63, and KI-67 was similar in HUT from the three different groups. The p63 expression in myoepithelial cells showed discontinuous pattern in the majority of HUT, different from continuous expression in normal lobules. Nuclear expression of p53 and p21 was frequently higher expressed in IMC and very rare in HUT. We also found cytoplasmic expression of p21 in benign hyperplastic lesions and in neoplastic cells of IMC. Conclusion: Our data failed to demonstrate different expression of cell cycle related proteins in HUT from patients with and without breast cancer. However, we found discontinuous expression of p63 in myoepithelial cells around HUT adjacent to carcinomas and cytoplasmic expression of p21 in epithelial cells of hyperplastic foci. Further studies are needed to determine how these subgroups relate to molecular abnormalities and cancer risk.
Breast Cancer Research and Treatment, 2003
Molecular markers predicting response to preoperative chemotherapy would be of major clinical relevance in breast cancer. Therefore, we studied the relationship between the expression of cell cycle regulatory proteins and clinical outcome in breast cancer patients receiving preoperative chemotherapy. Expression of p2lWaf1, p27KiP1, p53, cyclin D3 and Ki-67 was determined in breast carcinomas by means of immunohistochemistry both prior and after preoperative chemotherapy. Expression data were compared with both clinical parameters and response to preoperative chemotherapy with either cyclophosphamide/methotrexate/5-fluorouracil (CMF, n = 29) or epirubicin/docetaxel (ED, n = 36). In paired samples before and after preoperative chemotherapy, the percentage of p21Waf1, p27Kip1, p53 and cyclin D3 positive nuclei of tumor cells in postchemotherapy specimens was significantly higher than the percentage in prechemotherapy samples but no change in Ki-67 expression was observed. High Ki-67 expression (p = 0.02), negative estrogen receptor status (p = 0.01) and negative progesterone receptor status (p = 0.04) were associated with complete pathologic response to chemotherapy, whereas the other markers did not predict response. In conclusion, expression levels of p21Waf1, p27Kip1, p53 and cyclin D3 significantly increased after preoperative chemotherapy in breast carcinomas but only high Ki-67 expression, negative estrogen receptor status and negative progesterone receptor status were associated with complete pathologic response to preoperative chemotherapy.
Protein expression patterns of cell cycle regulators in operable breast cancer
PLOS ONE
Background-Aim To evaluate the prognostic role of elaborate molecular clusters encompassing cyclin D1, cyclin E1, p21, p27 and p53 in the context of various breast cancer subtypes. Methods Cyclin E1, cyclin D1, p53, p21 and p27 were evaluated with immunohistochemistry in 1077 formalin-fixed paraffin-embedded tissues from breast cancer patients who had been treated within clinical trials. Jaccard distances were computed for the markers and the resulted matrix was used for conducting unsupervised hierarchical clustering, in order to identify distinct groups correlating with prognosis. Results Luminal B and triple-negative (TNBC) tumors presented with the highest and lowest levels of cyclin D1 expression, respectively. By contrast, TNBC frequently expressed Cyclin E1,
Cancer research, 1997
Breast carcinomas < or = 1 cm in size (T1a,b) are being detected more frequently as a result of screening. Because traditional prognostic parameters are either lacking (tumor size) or rare (nodal metastases), a marker(s) is needed to identify the subset of patients who could benefit from adjuvant therapy. A retrospective series of 202 patients with stage T1a,b invasive breast carcinomas was evaluated. The clinicopathological features (age, histological grade, extensive in situ carcinoma, hormone receptor status, and nodal metastasis) as well as microvessel density and the expression of c-erb-B2, p53, MIB-1/Ki-67, and cdc25B were assessed. In addition, expression of the cell cycle inhibitor p27 was evaluated. Nineteen patients (18% of patients who had axillary dissection) had locoregional lymph node metastases. Forty-two % of them died of disease (median survival, 112 months), whereas mortality was 11% in node-negative patients (median survival, 168 months; P = 0.0055). Patients w...
Virchows Archiv, 2016
We aimed to analyze to what extent expression of four cell cycle regulation markers-minichromosome maintenance protein (MCM2), Ki-67, cyclin A, and phosphohistone-H3 (PHH3)-predict response to primary systemic therapy in terms of pathological complete remission (pCR). In search of an accurate and reproducible scoring method, we compared computer-assisted (CA) and routine visual assessment (VA) of immunoreactivity. We included 57 patients with breast cancer in the study. The cell cycle markers were detected using immunohistochemistry on pre-therapy core biopsy samples. Parallel CA (validated by manual labeling) and standard VA were performed and compared for diagnostic agreement and predictive value for pCR. CA and VA results were dichotomized based on receiver operating characteristic analysis defined optimal cutoff values. "High" was defined by staining scores above the optimal cutoff, while "low" had staining scores below the optimal cutoff. The CA method resulted in significantly lower values for Ki-67 and MCM2 compared to VA (mean difference, −3.939 and −4.323). Diagnostic agreement was highest for cyclin A and PHH3 (−0.586 and −0.666, respectively). Regardless of the method (CA/VA) used, all tested markers were predictive of pCR. Optimal cutoff based dichotomization improved diagnostic agreement between the CA and VA methods for every marker, in particular for MCM2 (κ = 1, p < 0.000). Cyclin A displayed excellent agreement (κ = 0.925; p < 0.000), while Ki-67 and PHH3 showed good agreement (κ = 0.789, p < 0.000 and κ = 0.794, p < 0.000, respectively). We found all cell cycle markers (Ki-67, MCM2, cyclin A, and PHH3) predictive of pCR. Diagnostic agreement between CA and VA was better at lower staining scores but improved after optimal cutoff based dichotomization.
Cellular oncology : the official journal of the International Society for Cellular Oncology, 2006
Deregulation of cell cycle control is a hallmark of cancer. The primary cyclins (A, B1, D1, D3 and E) are crucial for cell cycle progression. Secondary cyclins (C and H) have putative indirect effects on cell cycle propulsion and are not previously evaluated in breast cancer. We have examined protein expression and gene amplification of cyclins in breast carcinomas and correlated the findings with clinical follow-up data. We have previously demonstrated that over-expression of cyclin A is associated with poor prognosis in breast cancer patients. In this study we wanted to evaluate the mechanisms behind overexpression of cyclin A, as well as the impact of other cyclins, both at the gene level and at the protein level, on prognosis of breast cancer patients. The impact of TP53 gene mutations on gene amplification of cyclins was also evaluated. Real-Time Quantitative PCR was used to detect gene amplification of cyclins in tumour tissue from 86 patients operated for invasive breast carc...