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C E Gillett

Publications and source records attributed to C E Gillett.

At least 19 recordsLinked to original sources
PubMed2001

Retention of the expression of E-cadherin and catenins is associated with shorter survival in grade III ductal carcinoma of the breast.

Many studies have investigated the relationship between the E-cadherin/catenin axis and breast cancer biology and yet, unlike the studies in other tumour systems, which have shown a relationship between down-regulation and poor survival, no clear association has emerged in breast. Since accumulating evidence suggests that ductal carcinoma of no special type (NST) represents a diverse group of biologies, this study has focused on grade III ductal carcinoma, in order to reduce the heterogeneity of the study population. A total of 470 breast tumours were studied. Consecutive sections were labelled with antibodies which recognize E-cadherin and the arm proteins with which it interacts: alpha-, beta-, and gamma-catenin. Membrane-bound and cytoplasmic E-cadherin and membrane-bound alpha-catenin expression were associated with a positive oestrogen receptor (ER) status, gamma-catenin with a negative ER status, and, surprisingly, all three with poor survival. Taken together, these findings suggest that a conserved E-cadherin/catenin axis may play a part in determining adverse outcome in grade III breast carcinoma.

Adult↗
PubMed2001

The pattern of expression of the microtubule-binding protein RHAMM/IHABP in mammary carcinoma suggests a role in the invasive behaviour of tumour cells.

Intracellular hyaluronic acid binding protein (RHAMM/IHABP), which was recently identified as a novel member of the microtubule-associated protein (MAP) family, has the capacity to interact not only with microtubules but also with microfilaments. The molecule, which is known to be expressed in mammary carcinoma cells, might, through virtue of its intracellular interactions, influence tumour cell morphology and motility. This possibility was examined in a series of 189 mammary carcinomas by immunohistochemistry, using a polyclonal antibody to RHAMM/IHABP. Tumours were selected to include approximately equal numbers of consecutive grade I, II and III ductal carcinomas and invasive lobular carcinomas. Higher grade tumours had significantly lower expression of RHAMM/IHABP in the cytoplasm (p=0.02), but significantly increased expression in trabeculae (p=0.002) and further enhancement at the tumour island edges (p=0.002). Tumours of infiltrating lobular type had stronger expression in the overall cytoplasm (p=0.02) and trabeculae (p=0.08) than carcinomas of ductal type. The presence of strong trabecular expression was associated with a reduced overall survival time (p=0.017). These results suggest that RHAMM/IHABP expression may contribute to the motility and invasiveness of a tumour cell sub-population in breast cancers.

Adult↗
PubMed2000

Association between loss of heterozygosity of BRCA1 and BRCA2 and morphological attributes of sporadic breast cancer.

Germline mutations in the breast cancer-associated genes BRCA1 and BRCA2 confer a lifetime risk of malignancy. Distinctive morphological features have been attributed to these familial tumours; however, in sporadic breast cancer, the inter-relationship between loss of heterozygosity (LOH) of these loci and tumour morphology remains to be fully elucidated. We studied a series of 120 sporadic breast carcinomas using microsatellite markers to identify LOH of BRCA1, BRCA2, p53 and PTEN. The associations between loss at each of the loci were examined and related to tumour morphology. LOH of the 4 loci did not occur independently; there were highly significant associations between LOH of BRCA1 and both BRCA2 (p < 0.001) and p53 (p < 0.001). LOH at all 4 loci was significantly associated with a high degree of nuclear pleomorphism. Tumours with LOH of BRCA1 also had high mitotic indices, few tubules and a paucity of DCIS, all of which are morphological features similar to those described for familial cases. Following Bonferroni's correction for multiple tests, we found that the tumours with LOH of BRCA1 were still significantly associated with a high mitotic index (p = 0.0006) and a high degree of nuclear pleomorphism (p = 0.001).

BRCA2 Protein↗
PubMed2000

Nuclear expression of the c-erbB-4/HER-4 growth factor receptor in invasive breast cancers.

The prevalence and sites of expression of the c-erbB-4 receptor have been determined by immunocytochemical staining in a series of 178 human breast cancers. Most tumors displayed cytoplasmic staining of variable intensity. When compared with adjacent normal tissue, 32 cases (18%) showed lower than normal expression, and 13 (7%) showed greater than normal expression. Nuclear immunoreactivity, confirmed by two different antibodies, was present in 87 cancers (49%) but was found in normal adjacent breast epithelial cells in <5% of cases. There were no significant associations with cytoplasmic or membrane immunoreactivity, but cases showing nuclear expression in >25% of cells were associated with good histological grade, epidermal growth factor receptor expression, c-erbB-3 positivity, cripto, amphiregulin, and transforming growth factor-alpha overexpression.

Amphiregulin↗
PubMed2000

A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer cells.

The helix-loop-helix protein Id-1 inhibits the activity of basic helix-loop-helix transcription factors, and is an important regulator of cell growth and tissue-specific differentiation. We have shown (P. Y. Desprez et al., Mol. Cell. Biol., 18: 4577-4588, 1998) that ectopic expression of Id-1 inhibits differentiation and stimulates the proliferation and invasiveness of mouse mammary epithelial cells, and that there is a correlation between the levels of Id-1 protein and the aggressiveness of several human breast cancer cell lines. Here, we show that aggressive and metastatic breast cancer cells express high levels of Id-1 mRNA because of a loss of serum-dependent regulation that is mediated by a 2.2-kb region of the human Id-1 promoter. Three lines of evidence suggest that unregulated Id-1 expression may be an important regulator of the aggressive phenotype of a subset of human breast cancer cells: (a) a constitutively expressed Id-1 cDNA, when introduced into a nonaggressive breast cancer cell line (T47D), conferred a more aggressive phenotype, as measured by growth and invasiveness; (b) Id-1 was an important mediator of the effects of sex steroid hormones on T47D cell proliferation. Estrogen stimulated proliferation and induced Id-1 expression, whereas progesterone inhibited proliferation and repressed Id-1 expression. Progesterone repressed Id-1 expression, at least in part by repressing transcription. Most importantly, an antisense oligonucleotide that reduced Id-1 protein levels reduced the ability of estrogen to stimulate cell proliferation, whereas constitutive Id-1 expression rendered cells refractory to growth inhibition by progesterone; and (c) using a limited number of breast cancer biopsies, we showed that Id-1 was more frequently expressed in infiltrating carcinomas compared with ductal carcinomas in situ. Our results suggest that Id-1 can control the malignant progression of breast cancer cells, particularly that mediated by sex steroid hormones. Moreover, Id-1 has the potential to serve as a marker for aggressive breast tumors.

Animals↗
PubMed2000

Cell cycle proteins do not predict outcome in grade I infiltrating ductal carcinoma of the breast.

Infiltrating ductal mammary carcinomas are histologically graded according to their extent of differentiation. Well-differentiated, 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 metastasize, 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.

Adult↗
PubMed2000

Multiple tissue core arrays in histopathology research: a validation study.

The use of multiple tissue arrays allows the examination of large cohorts of tumour tissue with economies of material and technical resources. It also permits the direct comparison of tissues on the same slide. In the present study, a series of 157 breast cancers was labelled with antibodies which recognize oestrogen (ER) and progesterone (PR) receptors and the staining obtained on whole tissue sections was compared with that from a series of multicore arrays. A highly significant association was found between the staining scores (0-7) obtained from the individual tissue sections and from the multicore arrays, although there was some discordance between the receptor status (positive/negative) of the whole section and the tissue core in 5% of cases for ER and in 6.5% of cases for PR. Multiple tissue cores represent an attractive way of dealing with large cohorts of tumours for research studies, because of the significant reduction in reagents and technical time required and the overall speed with which a study can be completed. A proportion of individual tissue cores were not representative of the diagnostic section, which limits the value of multicore arrays as a tool for patient management. However, the technique provides an efficient way of assessing the potential predictive value of novel proteins in different tumour types and in large cohorts.

Biomarkers, Tumor↗
PubMed2000

Molecular markers for predicting prostate cancer stage and survival.

OBJECTIVE: To assess several molecular markers (detected by immunohistochemistry, IHC) to determine whether they can be used to improve the prognostic value of histological grade alone in predicting the behaviour of prostate cancer. PATIENTS AND METHODS: Tumour tissue was retrieved from 156 men in whom tumour grade, stage and survival were known. The outcome measures were: (i) local stage (T-stage, organ-confined vs extraprostatic); (ii) metastatic status (M-stage, bone metastasis vs no bone metastasis); and (iii) survival. The IHC markers used were chosen to provide a broad representation of various aspects of tumour biology, i.e. the androgen receptor (AR) and oestrogen receptor (ER), adhesion molecules (E-cadherin), proliferation markers (MIB-1), tumour-suppressor genes (TP53 and the retinoblastoma gene product, Rb) and other novel cancer-related proteins (cyclin D1 and the breast cancer susceptibility gene product, BRCA2). All factors were assessed using logistic regression and Cox proportional-hazards survival models for predictive value, after adjusting for effects. RESULTS: MIB-1, ER, cyclin D1 and E-cadherin all showed close statistically significant univariate associations with histological grade. Univariate analysis also identified close statistically significant associations between T-stage and both MIB-1 and E-cadherin. Likewise, there were close univariate associations for both M-stage and survival, and MIB-1, cyclin D1 and ER. Logistic regression modelling identified MIB-1, cyclin D1 and ER as statistically significant predictors of M-stage and, once MIB-1 was entered into the model, the effects of grade no longer made a significant contribution. MIB-1 was a significant predictor for T-stage, but the effects of grade remained significant in this model. Cox proportional-hazards modelling identified MIB-1, cyclin D1 and ER as being statistically significant predictors of survival, after adjusting for grade. After adjusting for both grade and MIB-1, the effects of cyclin D1 and ER were no longer statistically significant. Excess MIB-1, cyclin D1 or ER expression tended to be present within the most poorly differentiated and advanced-stage lesions; this provides an inherent instability to the models described. TP53, Rb, AR and BRCA2 were of limited prognostic value. CONCLUSIONS: MIB-1, ER and cyclin D1 provide prognostic information that is clearly independent of grade. However, their true clinical value is probably limited because they are expressed mainly in the most advanced lesions. Nevertheless, MIB-1 expression is of sufficient value to warrant inclusion in future prognostic models. Furthermore, the expression of cyclin D1 and ER may reflect aspects of tumour biology that individually are worthy of further investigation. However, none of the IHC markers used in this study can be recommended for use in routine histological preparations.

Adult↗
PubMed1999

Survival of premenopausal breast carcinoma patients in relation to menstrual cycle timing of surgery and estrogen receptor/progesterone receptor status of the primary tumor.

BACKGROUND: Premenopausal breast carcinoma patients who undergo tumor excision during the follicular phase of their menstrual cycle may have a significantly worse prognosis than those whose tumors are excised in other phases of the menstrual cycle. METHODS: Outcome was determined in a series of 112 premenopausal women with operable breast carcinoma in relation to the timing of surgery within the menstrual cycle and the estrogen receptor (ER) and progesterone receptor (PR) status of their primary tumors as determined by immunohistochemistry. RESULTS: Those patients with ER positive tumors who underwent surgery in the early and luteal phase of the cycle had a significantly better survival than women with ER negative tumors (chi-square test = 15.56; P < 0.001). This also was true for PR status (chi-square test = 18.21; P < 0.001). After follicular phase surgery, tumor receptor status had no effect on overall survival. Patients with the best prognosis had ER/PR positive tumors excised on Days 0-2 and 13-32 but even those women with ER or PR negative tumors removed during the luteal phase of their menstrual cycle fared better than patients whose tumors were removed during the follicular phase. CONCLUSIONS: There was a better survival rate for patients with both ER/PR positive and negative tumors treated during the luteal phase of the menstrual cycle. This could be the result of progesterone acting on the surrounding peritumoral normal tissue, thereby exerting a straitjacket effect and improving cohesion of the primary carcinoma. Unopposed estrogen in the follicular phase of the cycle may enable more tumor emboli to escape and successfully establish micrometastases.

Breast Neoplasms↗
PubMed1999

Effect of c-erbB(2) and estrogen receptor status on survival of women with primary breast cancer treated with adjuvant cyclophosphamide/methotrexate/fluorouracil.

We have investigated the relationship between c-erbB(2) status, estrogen receptor (ER) status and outcome in 274 women with node-positive breast cancer who, following excision and axillary clearance, were randomized to receive either 6 cycles of cyclophosphamide/methotrexate/fluorouracil (CMF) (n = 129) or no such treatment (n = 145). Follow-up data (median 13.3 years) were available on all patients. CMF improved relapse-free and overall survival of all women. The greatest benefit was seen in women with ER-negative tumors; the median overall survival of those given CMF was 11.6 years compared with only 2 years for the control group. For the women with ER-positive tumors the median overall survival of the CMF-treated women was 11.3 years compared with 7.7 years in the control group. When benefit from CMF was examined in relation to c-erbB(2) status, the women with c-erbB(2)-negative tumors who received CMF had a median overall survival of 12.7 years compared with only 7.3 years for the c-erbB(2)-negative women in the control group. The improvement in survival was less marked in the women with c-erbB(2)-positive tumors; median overall survival was 6.1 years for those who received CMF compared with 4.4 years for women in the control group. All women benefited from adjuvant CMF chemotherapy, those with ER-negative tumors benefiting the most. Int. J. Cancer (Pred. Oncol.) 84:354-359, 1999.

Adult↗
PubMed1999

Cyclin-dependent kinase inhibitor p27Kip1 expression and interaction with other cell cycle-associated proteins in mammary carcinoma.

p27, cyclin D1, and retinoblastoma (Rb) protein have been demonstrated using immunohistochemistry in 189 cases of primary breast carcinoma with long-term follow-up. There was a statistically significant association between the expression of p27 and both cyclin D1 and the retinoblastoma gene product (pRb), corresponding to their close interactions in regulating the G1/S transition in the cell cycle. Low levels of p27 were seen in high-grade, rapidly proliferating, oestrogen receptor-negative tumours. In univariate analysis, low p27 expression was associated with a reduced relapse-free and overall survival. In multivariate analysis, p27 was not an independent predictor of survival when either histological grade or proliferative activity (S-phase fraction) was included in the model. When the combined expression of p27 and cyclin D1 was related to survival, patients with high levels of p27, regardless of their cyclin D1 status, did well, whilst those with low p27 had a poor outcome. The only exception, in the latter group, was patients with tumours expressing high levels of cyclin D1, who did as well as the high p27 group. We have shown that in clinical material p27 expression is associated with proliferative activity and while univariate analysis shows it to be a significant indicator of prognosis, this significance is lost in multivariate analysis when traditional prognostic factors are included in the model. The interest in p27 expression in mammary carcinoma lies in its behaviour when examined in combination with other G1 cell cycle regulators.

Biomarkers, Tumor↗
PubMed1999

The biological and prognostic significance of cell polarity and E-cadherin in grade I infiltrating ductal carcinoma of the breast.

Grading of breast cancer based on the modified Scarff, Bloom, and Richardson system provides invaluable prognostic information. Recent evidence suggests that most tumours do not usually progress between grades and that groups of tumours within each grade are biologically distinct. This study has explored one potential aspect of biological tumour heterogeneity within grade by examining the relationship between cell polarity, the cell adhesion molecule E-cadherin, a major effector of cell polarity, and outcome, in 149 grade I infiltrating ductal breast carcinomas. Polarity was evaluated by studying the degree to which three features of polarized epithelial cells-nuclear ordering, basal positioning of nuclei within cells, and apical snouting/blebbing-were present in these tumours. E-cadherin expression was investigated using the antibody HECD-1. A low degree of tubule formation was correlated with poor nuclear ordering ( p< 0.01). The three histological features-nuclear ordering, basal nuclei, and apical blebbing-were all correlated with each other (all p< 0.0001). Polarity measurements did not correlate with survival. E-cadherin expression did not correlate with polarity and negative tumours were still able to form tubules. Surprisingly, strong E-cadherin immunostaining correlated with poor survival, tumour size, and nodal status. On univariate parametric (Weibull) survival models, high E-cadherin scores and tumour size were both significant predictors of survival in this group.

Adult↗
PubMed1998

Immunohistochemical expression of BRCA2 protein and allelic loss at the BRCA2 locus in prostate cancer. CRC/BPG UK Familial Prostate Cancer Study Collaborators.

Many epidemiological studies have reported an association between breast and prostate cancer. BRCA2 functions as a tumour-suppressor gene in about 35% of large familial breast-cancer clusters; its role in the pathogenesis of sporadic breast cancer is less clear. We have evaluated immunohistochemical expression of BRCA2 protein and allelic loss of markers at the BRCA2 locus in tissue derived both from sporadic and from familial cases of prostate cancer. Immunohistochemical analysis was performed in 167 paraffin-embedded archival specimens. Normal prostate and 75% (120/160) of prostate-cancer tissue did not express BRCA2 protein. However, 25% (40/160) of cancer cases did express patchy staining; of these, 17% (2711 60) expressed positive nuclear staining in normal glandular tissue adjacent to tumour (either in addition to, or, independent of tumour). Allelic loss is the hallmark of a tumour-suppressor gene. Markers flanking (D13S267, D13S260) and within (D13S171) the BRCA2 gene indicated allelic loss in at least one locus in 23% (17/73) of tumours analyzed. There was no difference in the rates of allelic loss between sporadic and familial tumours, nor was there any association between immunohistochemical staining and allelic loss. Although immunohistochemical staining provided no useful prognostic information, allelic loss at BRCA2 was shown in univariate analysis to be associated with poorer survival (log-rank test, p = 0.046).

BRCA2 Protein↗
PubMed1998

Retinoblastoma and p16 proteins in mammary carcinoma: their relationship to cyclin D1 and histopathological parameters.

The cell cycle-associated retinoblastoma protein (pRb) and p16 protein were demonstrated using immuno-histochemistry on paraffin sections from 192 cases of invasive breast carcinoma. Abnormal expression of pRb was defined as negative staining and was seen in 17% of tumours. Such abnormal expression was significantly more frequent in tumours with negative oestrogen receptor (ER) status. There was also a trend for tumours which were negative for pRb to be grade III ductal carcinomas. There was no association between p16 staining and any histopathological parameter, though, surprisingly, log-rank analysis showed that strong staining was associated with a poor outcome. There was a significant inverse relationship between pRb and p16 expression and a significant positive association between pRb and cyclin D1. In a Cox multivariate analysis, which included cyclin D1, neither pRb nor p16 was an independent predictor of patient outcome.

Breast Neoplasms↗
PubMed1998

Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia.

Experimental studies suggest that cyclin D1 is a potential oncogene but in clinical studies of invasive breast cancer, overexpression of cyclin D1 is found to be associated with oestrogen receptor (ER) expression and low histological grade, both markers of good prognosis. Immunohistochemistry has been used to examine the relationship between cyclin D1 expression and differentiation in 36 cases of ductal carcinoma in situ (DCIS) and the interrelationship between expression of cyclin D1, its associated protein product of the retinoblastoma gene (pRb), and ER, in this group of cases. The expression of these markers has also been examined in nine cases of atypical ductal hyperplasia (ADH) and these results have been compared with the levels of expression seen in DCIS. Cyclin D1 overexpression was found in 23/36 (64 per cent) cases of DCIS and, in contrast to invasive carcinoma, there was no relationship with either differentiation or ER expression. The level of pRb expression was significantly associated with cyclin D1 expression (rS = 0.49, P = 0.001) and only two cases (6 per cent) were pRb-negative. There was no association between pRb and differentiation of DCIS or ER status. In contrast to DCIS, only one case of ADH showed overexpression of cyclin D1 (Mann-Whitney U-test, P = 0.02). All cases of ADH were ER-positive and showed moderate pRb staining, similar to that seen in well-differentiated DCIS. These results provide further evidence that overexpression of cyclin D1 plays a role early in carcinogenesis.

Adult↗
PubMed1998

Cyclin D1 in breast cancer.

Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over-expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c-erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over-expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over-expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.

Animals↗
PubMed1998

Cell proliferation measured by MIB1 and timing of surgery for breast cancer.

We have investigated the use of the antibody MIB1 as a proliferative and prognostic marker in breast cancer and whether changes in proliferative activity could account for differences in prognosis of premenopausal women operated on during different phases of the menstrual cycle. MIB1 expression was strongly correlated with S-phase fraction and histological grade. There was no difference in MIB1 scores between different phases of the menstrual cycle. Both MIB1 score and timing of surgery correlated significantly with duration of survival, while the two together were even stronger predictors of overall survival. Women with slowly proliferating tumours surgically removed in the luteal phase had a very good prognosis, whereas women with rapidly proliferating tumours excised at other times of the cycle had a worse prognosis.

Adult↗