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PubMed2000

Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase.

The blockade of epidermal growth factor receptor (EGFR) function with monoclonal antibodies has major antiproliferative effects against human tumors in vivo. Similar antiproliferative effects against some of these same tumors have also been observed with specific inhibitors of the EGFR-associated tyrosine kinase. One such inhibitor, the p.o. active ZD1839 (Iressa), has pronounced antiproliferative activity against human tumor xenografts. We now show that coadministration of ZD1839, as with anti-EGFR, will enhance the efficacy of cytotoxic agents against human vulvar (A431), lung (A549 and SK-LC-16 NSCL and LX-1), and prostate (PC-3 and TSU-PR1) tumors. Oral ZD1839 (five times daily x 2) and cytotoxic agents (i.p. every 3-4 days x 4) were given for a period of 2 weeks to mice with well-established tumors. On this schedule, the maximum tolerated dose (150 mg/kg) of ZD1839 induced partial regression of A431, a tumor that expresses high levels of EGFR, 70-80% inhibition among tumors with low but highly variable levels of EGFR expression (A549, SKLC-16, TSU-PR1, and PC-3), and 50-55% inhibition against the LX-1 tumor, which expresses very low levels of EGFR. ZD1839 was very effective in potentiating most cytotoxic agents in combination treatment against all of these tumors, irrespective of EGFR status, but dose reduction of ZD1839 below its single-agent maximum tolerated dose was required for optimum tolerance. The pronounced growth inhibitory action of the platinums, cisplatin and carboplatinum, as single agents against A431 vulvar, A549 and LX-1 lung, and TSU-PR1 and PC-3 prostate tumors was increased several-fold when ZD1839 was added, with some regression of A431 and PC-3 tumors. Although the taxanes, paclitaxel or docetaxel, as single agents markedly inhibited the growth of A431, LX-1, SK-LC-16, TSU-PR1, and PC-3, when combined with ZD1839, partial or complete regression was usually seen. Against A549, the growth inhibition of doxorubicin was increased 10-fold (>99%) with ZD1839. The folate analogue, edatrexate, was highly growth inhibitory against A549, LX-1, and TSU-PR1, whereas edatrexate combined with ZD1839 resulted in partial or complete regression in these tumors. Against the A431 tumor, paclitaxel alone either was highly growth inhibitory or induced some regression, but when combined with ZD1839, pronounced regression was obtained. Combination with gemcitabine neither added nor detracted from baseline cytotoxic efficacy, whereas ZD1839 combined with vinorelbine was poorly tolerated. Overall, these results suggest that potentiation of cytotoxic treatment with ZD1839 does not require high levels of EGFR expression in the target tumors. They also suggest significant clinical benefit from ZD1839 in combination with a variety of widely used cytotoxic agents.

Aminopterin↗

PubMed2001

[Increase of EGFR expression by Epstein-Barr virus LMP1 in nasopharyngeal carcinoma cells].

OBJECTIVE: To investigate the effect of LMP1 on the expression of epidermal growth factor receptor (EGFR) in HNE2-LMP1 cells. METHODS: Stable transfectant HNE2 cell line expressing LMP1 (HNE2-LMP1) or its mutants (HNE2 del 187-351, HNE2 1-231, HNE2 1-187) were used as cell models. The expression of EGFR was detected by Western blot method. The characteristics of EGFR expression were analyzed when HNE2-LMP1 LMP1 cells were transiently transfected with TRAF1, 2, 3 or TRAF1, 2, 3 dominant negative mutants (DN-TRAF1, 2, 3). The growth characteristics of HNE2-LMP1 and vector controls were analyzed on serum-free media supplemented with EGF. RESULTS: Stable expression of LMP1 in HNE2 cells increased the expression of EGFR. LMP1 CTAR1 domain, being identical to the TRAF interaction domain, was essential to the induction of EGFR. The CTAR2 domain did not induce expression of EGFR. Overexpression of either TRAF1, 3 or an dominant negative mutant of TRAF1, 3 inhibited the expression of EGFR, while TRAF2 or negative mutants of TRAF2 did slightly so. In HNE2-LMP1 cells, LMP1 expression increased the proliferative response to EGF while the vector control cells exhibited very low level of viability and did not proliferate. CONCLUSION: The induction of EGFR by LMP1 CTAR1 may be an important component of EBV infection via an TRAF1, 2, 3 mechanism in the epithelial cells and may contribute to the development of epithelial malignancies such as nasopharyngeal carcinoma.

Blotting, Western↗

PubMed2004

[Expression and significance of EGF mRNA and EGFR mRNA in hepatocellular carcinoma].

BACKGROUND & OBJECTIVE: Many evidences demonstrated that the epidermal growth factor receptor (EGFR) subfamily played an important role in they initiation and progression of various cancers. But it is not clear whether there is a relationship between EGFR and hepatocellular carcinoma (HCC). The aims of the present study were to explore the expression and significance of the epidermal growth factor (EGF) mRNA and EGFR mRNA in human HCC tissues. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) was employed to determine the expression of EGF mRNA and EGFR mRNA in 60 HCC tissues and their adjacent liver tissues. RESULTS: The positive rate of EGF mRNA was significantly lower in the HCC tissue (60%, 36/60) than in the adjacent liver tissue (80%, 48/60) (P< 0.05). The positive rate of EGFR mRNA in the HCC tissue (60%, 36/60) was markedly higher than in the adjacent liver tissue (41.67%, 25/60) (P< 0.05). The expression of EGFR mRNA in the HCC tissue was significantly correlated with the clinical stage, the portal vein tumor thrombus, the presence of extrahepatic metastasis, and the recurrence of tumor, the number of tumor, but not correlated with the diameter of tumor, the level of serum alpha-fetoprotein (AFP), the differentiation of tumor and the liver cirrhosis in the adjacent tissue. The detectable rate of EGF mRNA was correlated with the diameter of tumor but not correlated with the clinical stage, the portal vein tumor thrombus, the presence of extrahepatic metastasis, the recurrence of tumor, the number of tumor, the level of serum AFP, the differentiation of tumor and the liver cirrhosis in the adjacent tissue. CONCLUSIONS: EGF may not be involved in the initiation and progression of HCC, whereas, EGFR relates to the initiation and progression and the recurrence of HCC. EGFR can be considered as a marker for predicting the metastasis and recurrence of HCC.

Adult↗

PubMed2005

Targeted inhibition of transient activation of the EGFR-mediated cell survival pathway enhances paclitaxel-induced ovarian cancer cell death.

Emerging studies have suggested that transient activation of the cell survival pathway may be the strategy for cancer cells to fight against chemotherapy and eventually mysteriously evade paclitaxel-induced cell death. Modulation of the EGFR-mediated survival pathway in addition to the utilization of paclitaxel renders a promise of better clinical management. The objective of this study was to understand the molecular mechanism of transient induction of EGFR-mediated cell survival by paclitaxel. We utilized ovarian cancer cell line, Caov3, cells to investigate the effect of paclitaxel on EGFR-mediated MAP kinase and AKT activation, and the expression of survivin. We found that paclitaxel transiently induced EGFR phosphorylation and ERK and AKT activation but not JNK and p38. Paclitaxel-induced ERK and AKT activity was inhibited by the EGFR inhibitor, PD153035; ERK inhibitor, U0126; and PI3 kinase inhibitor, LY294002, respectively. We observed that paclitaxel transiently induced expression of survivin in the early hours of treatment. Paclitaxel-induced survivin expression was inhibited by the EGFR inhibitor, PD153035. Inhibitors of EGFR, ERK and PI3 kinase all enhanced paclitaxel-induced cell death. We conclude that paclitaxel transiently transactivates EGFR, leading to activation of cell survival factors, such as ERK and AKT, and expression of survivin, which are all inclusively accountable for ovarian cancer cell resistance to paclitaxel treatment. A combination of these inhibitors with paclitaxel may be a better option for ovarian cancer treatment.

Antineoplastic Agents, Phytogenic↗

PubMed2006

Coexpression of the IGF-IR, EGFR and HER-2 is common in colorectal cancer patients.

Signalling via the insulin-like growth factor-I receptor (IGF-IR) has been associated with resistance to anti-epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2)-based therapies in the experimental system, but the coexpression and clinical significance of the IGF-IR, EGFR and HER-2 in cancer patients remains unclear. IGF-IR, EGFR, and HER-2 status was assessed retrospectively in tumour specimens from 87 Dukes' C colorectal cancer patients using immunohistochemistry. Sections were scored by the percentage of positive cells (membrane and cytoplasmic) and intensity of staining. The association between receptor coexpression and clinicopathological parameters and overall survival were evaluated using univariate and multivariate (Cox) analysis. Overall, 93, 83 and 89% of the cases expressed IGF-IR, EGFR and HER-2, respectively. While 60% of the cases expressed membranous IGF-IR, the expression of EGFR and HER-2 was predominantly cytoplasmic. Coexpression of the IGF-IR, EGFR and HER-2 was present in tumours from 75% of the patients. No significant association was found between the expression or coexpression of total IGF-IR, EGFR and HER-2 and clinicopathological parameters or overall survival. Our results indicate that coexpression of IGF-IR, EGFR and HER-2 is common in Dukes' C colorectal cancer, warranting further investigation on the co-targeting of such receptors in colorectal cancer patients.

Aged↗

PubMed2006

[Significance of EGFR and p-ERK expression in nasopharyngeal carcinoma].

OBJECTIVE: To detect the expression of EGFR and p-ERK in nasopharyngeal carcinoma (NPC) and investigate their clinical significance. METHODS: Immunohistochemistry LSAB method was adopted to detect the expression of EGFR and p-ERK. Statistical analysis was performed using SPSS statistical software package (10.0) to correlate their expression with clinical characteristics and prognosis. RESULTS: Positive staining for EGFR was observed in 39 of 55 cases (70.9%). The EGFR expression was correlated with clinical stage and gender. EGFR expression was correlated with poorer overall survival (OS) and shorter time to progression (TTP). Positive staining for p-ERK was observed in 29 of 55 cases (52.7%). There was a statistically significant association between positive p-ERK expression and advanced clinical stage. Positive p-ERK expression was correlated with poorer OS, disease-free survival (DFS) and TTP. EGFR expression was correlated with the expression of p-ERK. On multivariate analysis, age over 50 years was an independent poor prognostic factor for NPC. Both EGFR and p-ERK were not independent prognostic factors for NPC. CONCLUSION: Expressions of EGFR and p-ERK are detected in NPC. Their abnormally high expression signifies poor prognosis in NPC patients.

Age Factors↗

PubMedDate not supplied

Epidermal growth factor receptor (EGFR): mutational and protein expression analysis in gastric cancer.

BACKGROUND: Since specific epidermal growth factor receptor (EGFR) somatic mutations have been demonstrated to influence the response to anti-EGFR therapy in non-small cell lung cancer, EGFR gene mutational analysis of different types of neoplasm is under investigation. PATIENTS AND METHODS: EGFR protein expression and gene mutations in exons 18, 19 and 21 were investigated in 49 gastric adenocarcinomas. RESULTS: no specific EGFR gene mutations were detected, while EGFR positive staining was detected in 6% of the cases. CONCLUSION: Our findings indicate that in gastric adenocarcinoma, specific EGFR gene mutations are very rare or absent and the rate of EGFR protein expression is low.

Adenocarcinoma↗

PubMed1991

[Immunohistochemical study on the expression of epidermal growth factor receptor (EGFR) in human colorectal carcinomas].

The expression of epidermal growth factor receptor (EGFR) was studied immunohistochemically in 92 colorectal carcinomas: 21 early and 71 advanced. EGFR immunoreactivity was detected in 15 cases (16.3%) of colorectal carcinomas. All EGFR-positive cases was advanced carcinomas, while no EGFR immunoreactivity was found in early carcinomas. EGFR-positive cases were macroscopically 3.4 type and more than 2 cm in diameter. No significant correlation of EGFR expression with tumor location, stage, lymph node metastasis, degree of differentiation, and prognosis was found. All EGFR-positive cases was synchronous positive for the expression of EGF. These results suggest that EGFR may play an important role in tumor progression in cooperation with EGF.

Adult↗

PubMed1994

Immunohistochemical study of epidermal growth factor receptor (EGFR) in various types of renal injury.

Epidermal growth factor (EGF), a polypeptide with a potent mitogen activity, and its receptor [EGFR] have been previously identified in the kidney, but their expression in normal and diseased kidneys has not been fully elucidated. In order to evaluate EGFR in various histological types of renal injury, EGFR expression was studied by the immunohistochemical avidin-biotin complex (ABC) method with a monoclonal antibody EGFR1 on paraffin sections from 10 normal kidneys, 56 renal biopsies with various types of glomerulonephritis (GN), and 20 renal grafts with rejection. EGFR expression was observed in (a) 3 of 10 (30%) normal kidneys, (b) 17 of 39 (43.6%) renal biopsies with various types of GN mainly in membranous GN (57%) and in focal segmental glomerulosclerosis (FSG) (62.5%), (c) 6 of 17 (35.3%) biopsies with various types of systemic lupus erythematosus GN, and (d) 12 of 20 (60%) renal grafts with acute (42.9%) and chronic (69.2%) rejection. EGFR was mainly localized to the epithelial cells of the distal and collecting tubules and extraglomelar vessels, while it was observed less frequently in parietal epithelial cells and along glomerular basement membranes. Notably EGFR was detected in the epithelial cells adjacent to adhesions with Bowman's capsule and in the connective tissue of fibrocellular crescents. In conclusion, EGFR expression was observed more frequently in diseased than in normal kidneys. The increased incidence of EGFR expression in FSG, in chronic rejection, in small adhesions with Bowman's capsule and fibrocellular crescents suggest that EGF/EGFR may be correlated with a disturbed extracellular matrix production resulting in formation of early sclerotic lesions.

Basement Membrane↗

PubMedDate not supplied

Expression of epidermal growth factor receptor (EGFR) in breast cancer as related to clinical, prognostic and cytometric factors.

A series of 213 female breast carcinomas were analysed immunohistochemically for the expression of epidermal growth factor receptor (EGFR), with special emphasis on its possible prognostic significance. A total of 114/213 tumors (53.5%) were EGFR positive. EGFR was almost exclusively expressed in the cytoplasm of the cancer cells, but in a few cases, the cell membranes showed EGFR positive staining as well. EGFR expression was related to the histological grade of the tumours in that a linear decrease of the staining was found in parallel with the decreasing tumour differentation (P = 0.024). On the other hand, axillary lymph node status (P = 0.95), histological type (P = 0.60), tumor size (P = 0.87), DNA-index (P = 0.56), S-phase (P = 0.80), mitotic index (P = 0.72), or estrogen (ER) and progesterone receptor (PR) content (P = 0.45) did not show any statistical correlation with the EGFR expression. EGFR positivity as an independent factor, had little (if any) effect on the patients prognosis. Tumor size (P = 0.004), axillary lymph node involvement (P = 0.024) and PR positivity (P = 0.008) were the single most significant prognostic factors in multivariate survival analysis. The results indicate that, in clinical breast cancer, immunohistochemical assessment of EGFR provides no prognostic information additional to the well established prognostic factors.

Adult↗

PubMedDate not supplied

Tissue and serum c-erbB-2 and tissue EGFR in breast carcinoma: three years follow-up.

Amplification of erbB-1 and c-erbB-2 genes has been shown in human breast cancer. Expression of these protooncogenes results in production of epidermal growth factor receptor (EGFR) and c-erbB-2. Both are transmembrane receptors with tyrosine kinase activity. Recent data have indicated that the external domain of c-erbB-2 is shed into the culture supernatant of certain breast cancer cell lines and sera of breast cancer patients. A body of literature has shown that the overexpression of these receptors in malignant tissue and c-erbB-2 when shed into serum is associated with bad prognosis. In the present work, tissue EGFR and c-erbB-2 were determined in the membrane fractions of histopathologically verified malignant and normal tissues from the same breast of 94 patients. These values were also determined in 48 tissue specimens of benign mastopathies. Serum c-erbB-2 was quantified in breast cancer patients (n = 105), patients with benign breast disease (n = 48) and 30 apparently healthy women as controls. Patients were followed up by determination of serum c-erbB-2 for one year and clinically for three years to detect any distant metastasis or recurrence. The levels of tissue and serum c-erbB-2 and Estrogen receptors were significantly higher in the carcinomas and sera of breast cancer patients than benign breast diseases or normal controls. Follow-up, although short, of pre-operative serum c-erbB-2 showed a prognostic value (P = 0.007) better than that of tumor size (P = 0.04), EGFR (P = 0.18), nodal involvement (P = 0.25) and tissue c-erbB-2 (P = 0.85). The shedding of soluble fragments of c-erbB-2 into the serum seems to be a characteristic of the potentially malignant cell. The EGFR mean level, however, was significantly lower in malignant tissues than benign and normal ones. A new definition of EGFR status was developed. Accordingly, the recurrence of the disease was more frequent among patients with negative EGFR. The present work did not reveal any correlation between tissue, serum c-erbB-2 or EGFR on one hand and age, menopausal status, stage, histological type and grade of carcinomas and nodal involvement on the other hand. The present work showed an inverse correlation between estrogen receptor level and level of EGFR in malignant tissues.

Adult↗

PubMed2026

Targeting EGFR in cancer using Terminalia arjuna: An integrated In Silico, molecular dynamics, experimental validation, and network pharmacology study.

The Epidermal Growth Factor Receptor (EGFR) plays a pivotal role in 20-60% of cancer cases, including glioblastoma, lung adenocarcinoma, and head and neck squamous cell carcinoma, as reported in The Cancer Genome Atlas (TCGA) dataset. The present study employed an integrated in silico and experimental workflow to evaluate EGFR-targeted compounds from Terminalia arjuna. Drug-likeness and ADMET screening were performed, followed by molecular docking and 1000 ns molecular dynamics simulations. In vitro validation was conducted using cancer cell-based assays and network pharmacology to explore the molecular mechanisms associated with the identified compound. Screening shortlisted eight compounds from T. arjuna. Molecular docking identified Arjunaside C (-8.2 kcal/mol), Arjunapthanoloside (-7.7 kcal/mol), and Beta-sitosterol (-7.4 kcal/mol) as potential EGFR inhibitors compared to Erlotinib (-6.6 kcal/mol). Arjunapthanoloside formed more H-bonds and exhibited most stable interactions with EGFR. MD simulations at 1000 ns revealed lower RMSD, RMSF, SASA, and Rg values for the Arjunapthanoloside-EGFR complex, indicating enhanced stability. Direct binding validation was limited by the unavailability of purified Arjunapthanoloside; therefore, Arjuna extract was evaluated, which demonstrated potent cytotoxicity with an IC₅₀ of 9 µg/mL in H357 oral cancer cells. Flow cytometry confirmed apoptosis-mediated cell death by increased early- and late-apoptotic cell populations. Network pharmacology analysis further identified additional targets (MMP3, MMP7, MMP9, and HRAS) that are directly involved in various cancers. Overall, the findings provide new insights into the therapeutic potential of Arjunapthanoloside as a stable compound that interacts with EGFR from T. arjuna, highlighting its significance in EGFR-targeted anticancer research.

ErbB Receptors↗

PubMed2000

Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer.

Angiogenesis is esential for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and is an important component of the angiogenic stimulus in a range of human neoplasias. In addition to its mitogenic activities, VEGF has also been found to stimulate migration in macrophages via the flt-1 VEGF receptor. It has previously been shown that increased focal tumour macrophage infiltration is associated with increased angiogenesis and worsened relapse-free and overall survival in breast cancer. Macrophages are able to stimulate angiogenesis by their production of a range of factors including VEGF, tumour necrosis factor-alpha (TNF-alpha), and thymidine phosphorylase (TP). Thus, in breast cancer, VEGF could have a dual role in the regulation of angiogenesis, by direct mitogenic stimulation of endothelial cells, and also indirectly by attracting macrophages into avascular tumours. The purpose of this study was to localize VEGF protein in a series of 96 consecutive primary breast carcinomas and to determine its relationship to focal macrophage infiltration (macrophage index). These two variables were also compared with the pathological features of the tumours, as well as oestrogen receptor (ER), epidermal growth factor receptor (EGFR), microvessel density, macrophage index, and survival. An inverse relationship (p=0.0006) was noted between VEGF and EGFR, with high VEGF expression correlating with low EGFR levels. In the EGFR-negative group of cases (n=56), positive associations were observed between VEGF expression and macrophage index (p=0.005), ER (p=0.05), p53 (p=0. 006), tumour grade (p=0.02), and tumour necrosis (p=0.03). Macrophage counts were higher in EGFR-positive tumours (p=0.0006) and no associations were found between VEGF expression and increased microvessel density. These results show that in breast cancers there are two types of macrophage infiltrates, one associated with the presence of EGFR and low VEGF expression in tumours and the other with high VEGF expression in EGFR-negative tumours. VEGF expression may be an important factor in the recruitment of tumour-associated macrophages into breast carcinomas and may thus have an additional, indirect, pathway of angiogenic stimulation in this type of tumour.

Adult↗

PubMed2005

Genome wide analysis of transcript levels after perturbation of the EGFR pathway in the Drosophila ovary.

Defects in the epidermal growth factor receptor (EGFR) pathway can lead to aggressive tumor formation. Activation of this pathway during normal development produces multiple outcomes at the cellular level, leading to cellular differentiation and cell cycle activation. To elucidate the downstream events induced by this pathway, we used genome-wide cDNA microarray technology to identify potential EGFR targets in Drosophila oogenesis. We focused on genes for which the transcriptional responses due to EGFR pathway activation and inactivation were in opposite directions, as this is expected for genes that are directly regulated by the pathway in this tissue type. We perturbed the EGFR pathway in epithelial follicle cells using seven different genetic backgrounds. To activate the pathway, we overexpressed an activated form of the EGFR (UAS-caEGFR), and an activated form of the signal transducer Raf (UAS-caRaf); we also over- or ectopically expressed the downstream homeobox transcription factor Mirror (UAS-mirr) and the ligand-activating serine protease Rhomboid (UAS-rho). To reduce pathway activity we used loss-of-function mutations in the ligand (gurken) and receptor (torpedo). From microarrays containing 6,255 genes, we found 454 genes that responded in an opposite manner in gain-of-function and loss-of-function conditions among which are many Wingless signaling pathway components. Further analysis of two such components, sugarless and pangolin, revealed a function for these genes in late follicle cell patterning. Of interest, components of other signaling pathways were also enriched in the EGFR target group, suggesting that one reason for the pleiotropic effects seen with EGFR activity in cancer progression and development may be its ability to regulate many other signaling pathways.

Animals↗

PubMed2001

Estrogen suppression of EGFR expression in breast cancer cells: a possible mechanism to modulate growth.

Epidermal growth factor receptor (EGFR) is a transmembrane receptor whose overexpression in breast cancer predicts for poor prognosis and is inversely correlated with expression of estrogen receptor (ER). This study was designed to investigate whether estrogen plays an active role in suppression of EGFR expression in estrogen-responsive breast cancer cell lines expressing low levels of EGFR. Upon withdrawal of estrogen, EGFR mRNA and protein increased 3-6 fold in MCF-7, T47D, and BT474 ER+ breast cancer cells. This was reversible upon addition of estradiol back to the culture media, but only after prolonged treatment. Nuclear run-on assays and studies with the transcription inhibitor actinomycin D demonstrated that regulation is at the transcriptional level. These results indicate that in the presence of estrogen, ER+ breast cancer cells possess active mechanisms to suppress EGFR expression. Up-regulation of EGFR in response to estrogen depletion and growth inhibition could represent an attempt to rescue cell growth by utilizing an alternative pathway. Indeed, we found that estrogen-depleted breast cancer cells are more sensitive to the mitogenic effects of EGF and TGF-alpha, and simultaneous blockade of both estrogen and EGFR signaling pathways induced cell death. J. Cell. Biochem. Suppl. 36: 232-246, 2001.

Blotting, Western↗

PubMed1994

Expression of EGFR, HER-2/neu, P53, and PCNA in endometrioid, serous papillary, and clear cell endometrial adenocarcinomas.

Expression of four biologic markers was studied in 69 cases of endometrial cancer to identify their association with cell type, decreased survival, and increased tumor metastasis. Cell types included endometrioid (n = 45), serous papillary (n = 16), and clear cell (n = 8). Immunohistochemical stains were employed to detect the presence of epidermal growth factor receptor (EGFR), HER-2/neu, p53, and proliferating cell nuclear antigen (PCNA). Analysis revealed that EGFR was expressed in 49%, HER-2/neu in 59%, p53 in 9%, and PCNA in 16% of tumor specimens. HER-2/neu overexpression was significantly associated with depth of myometrial invasion. p53 and PCNA immunoreactivity significantly correlated with nonendometrioid histology, although PCNA was less specific in labeling these less favorable cell types. EGFR immunoreactivity also significantly correlated with nonendometrioid cell types and tumor metastases at time of diagnosis. Seventy-seven percent of patients with metastatic disease were EGFR-positive versus 36% positivity in patients with no evidence of metastases (P < 0.002). For patients with endometrioid adenocarcinoma, evidence of EGFR overexpression decreased survival from 89 to 69% (P < 0.04). In the serous papillary and clear cell category, EGFR positivity decreased survival from 86 to 27% (P < 0.03). EGFR strongly correlates with tumor metastasis and patient survival in endometrial cancer. Altered expression of this oncoprotein may serve as a guide to prognosis and treatment in these patients.

Adenocarcinoma↗

PubMed2002

Cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), and Her-2/neu expression in ovarian cancer.

OBJECTIVES: Cyclooxygenase-2 (COX-2) seems to be involved in critical steps of cancer onset and progression. Abnormalities of epidermal growth factor receptor (EGFR) and Her-2/neu have been actively investigated in ovarian cancer and associated with unfavorable clinical outcome. The involvement of COX-2 in ErbB family pathways has been proposed. We investigated by immunohistochemistry the expression of COX-2, EGFR, and Her-2/neu in a series of advanced primary ovarian cancers. METHODS: The study included 76 consecutive stage IIIC-IV ovarian cancer patients with measurable disease after first surgery. Immunohistochemistry was performed on paraffin-embedded sections with rabbit antiserum against COX-2, murine monoclonal antibody (MoAb) 300G9 against Her-2/neu, and monoclonal antibody 108 against EGFR. RESULTS: No association among COX-2, EGFR, and HER-2/neu was found. COX-2 positivity was found in a statistically significant higher percentage of unresponsive cases (80.0%) than in patients responding to chemotherapy (35.7%) (P = 0.0008). The association between COX-2 positivity and poor chance of response to treatment was retained in multivariate analysis. In the subgroup of patients who underwent explorative laparotomy COX-2-positive cases showed a shorter overall survival (P = 0.049). CONCLUSIONS: COX-2 could represent a possible new marker of sensitivity to platin-based chemotherapy in ovarian cancer. The lack of association of COX-2 with EGFR or Her-2/neu suggests that the ability of COX-2 to predict tumor sensitivity to chemotherapy is not dependent on EGFR or Her-2/neu status and could be independently associated with prognosis. In this context, the availability of agents able to specifically interfere with COX-2, Her-2/neu, or EGFR tyrosine kinase is of potential interest.

Cyclooxygenase 2↗

PubMed2005

Radiosensitivity of tumor cell lines after pretreatment with the EGFR tyrosine kinase inhibitor ZD1839 (Iressa).

BACKGROUND AND PURPOSE: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa) reduces survival and augments radiation response of certain tumor cells. The aim of this study was to identify cellular events that are associated with the modulation of radiosensitivity by ZD1839. MATERIAL AND METHODS: Three tumor cell lines (A549, H596, FaDu) were exposed to ionizing radiation, treatment with ZD1839, and combined treatment. Clonogenic cell survival was determined by colony assays, EGFR and transforming growth factor-(TGF-)alpha expression by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), cell cycle distribution and apoptosis by flow cytometry. RESULTS: In A549 and H596 cells ZD1839 had little effect on clonogenic growth, but survival curves revealed a radiosensitizing effect of 5 microM ZD1839 on A549 cells. Both cell lines expressed moderate amounts of EGFR mRNA and very low levels of TGF-alpha mRNA. FaDu cells expressed relatively high amounts of EGFR and TGF-alpha transcripts and showed marked inhibition of clonogenic growth, reduction of S-phase cells, and induction of apoptosis after treatment with 1 microM ZD1839 and combined treatment. Surprisingly, the subpopulation of FaDu cells surviving ZD1839 pretreatment was more radioresistant. Exposure to ZD1839 caused a decrease in EGFR mRNA expression in A549 cells, no change in H596, and even an increase in FaDu cells. CONCLUSION: The sensitivity to ZD1839 correlated with the EGFR expression level, an inhibition of cell proliferation, and induction of apoptosis in the cell lines analyzed. A radiosensitizing effect of ZD1839 was associated with downregulation of EGFR mRNA expression.

Adenocarcinoma↗