Clinical significance of cyclin D1 expression in patients with node-positive breast carcinoma treated with adjuvant therapy

Pelosio, Paola; Barbareschi, Mattia; Bonoldi, Emanuela; Marchetti, Antonio; Verderio, Paolo; Caffo, Orazio; Bevilacqua, P.; Boracchi, Patrizia; Buttitta, Fiamma; Barbazza, Renzo; Palma, Paolo Dalla; Gasparini, Giampietro

doi:10.1093/oxfordjournals.annonc.a010718

Cited by 51 publications

(32 citation statements)

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“…13,14 After several attempts at optimising mouse monoclonal and rabbit polyclonal antibodies to cyclin D1, we have attained reproducible results with the rabbit monoclonal antibody employing the protocol described by Cheuk et al 28 In contrast to other antibodies, the new rabbit anticyclin D1 monoclonal antibody shows a strong correlation with CCND1 gene amplification. However, in accordance with previous studies, 1,11,13,14,16,[19][20][21] cyclin D1 overexpression was still more pervasive than gene amplification. In the present study, 67.4% of the cases showed strong cyclin D1 expression, whereas only 11.6% showed very low levels or no expression of this cell cycle regulator.…”

Section: Discussionsupporting

confidence: 88%

“…Conflicting results on the prognostic impact of cyclin D1 overexpression and clinical outcome in breast cancer patients have been reported. 1,11,[16][17][18][19][20][21][37][38][39] Despite the known problems with commercially available anticyclin D1 antibodies, a considerable amount of data linking cyclin D1 overexpression with lack of response to tamoxifen have been published. 13,14 After several attempts at optimising mouse monoclonal and rabbit polyclonal antibodies to cyclin D1, we have attained reproducible results with the rabbit monoclonal antibody employing the protocol described by Cheuk et al 28 In contrast to other antibodies, the new rabbit anticyclin D1 monoclonal antibody shows a strong correlation with CCND1 gene amplification.…”

Section: Discussionmentioning

confidence: 99%

“…10,12,18 Cyclin D1 overexpression is reported to be more prevalent than amplification, with the reported frequency ranging from 28 to 83%. 1,2,11,13,14,16,[19][20][21][22][23] This variation has been linked with different antibodies, techniques and thresholds (cutoff points). Cyclin D1 overexpression, with or without CCND1 amplification, has received great attention in the literature in the last three years due to results of in vitro studies and data from clinical trials implicating cyclin D1 overexpression in resistance to tamoxifen treatment.…”

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Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis

et al. 2006

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Conflicting results on the prevalence of cyclin D1 ovexpression and its correlation with CCND1 amplification and outcome of breast cancer patients have been reported. Owing to limited sensitivity and specificity of most antibodies against cyclin D1, evaluation of cyclin D1 immunoexpression is reported to be problematic. The aims of this study were to assess the prevalence of cyclin D1 expression in breast carcinomas using the SP4 rabbit monoclonal antibody; to correlate cyclin D1 expression with amplification, assessed using chromogenic in situ hybridisation (CISH); and to analyse the relationship between CCND1 amplification and overexpression with clinicopathological parameters and outcome in a tissue microarray containing replicate tumour samples from 245 breast cancer patients. Immunohistochemistry for cyclin D1 was performed using the SP4 and the results were scored according to the Allred scoring system. CISH was carried out using the Zymed CCND1 SpotLight probe. CISH signals were counted in 60 morphologically unequivocal neoplastic cells. Amplification was defined as 45 signals per nucleus in more than 50% of cancer cells, or when large gene copy clusters were seen. Strong cyclin D1 expression and CCND1 amplification were found in 67.4 and 14.5% of the cases, respectively. A strong correlation between cyclin D1 overexpression and CCND1 amplification was demonstrated (Po0.0001). Cyclin D1 expression showed a positive correlation with hormone receptor expression (both ER and PgR, Po0.0001). An inverse correlation was observed between an immunohistochemical panel of 'basal-like' markers and both cyclin D1 overexpression (Po0.0001) and CCND1 amplification (Po0.0001). On univariate analysis cyclin D1 expression showed a correlation with longer overall survival (OS). Neither cyclin D1 nor CCND1 were independent prognostic factors for disease-free survival or OS. The results of this study confirm the association between cyclin D1 overexpression and positivity for hormone receptors and the lack of CCND1 amplification in basal-like breast carcinomas.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis

et al. 2006

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“…If we think of multiple, preneoplastic epithelial areas scattered throughout the organ, then the data could be interpreted to suggest that lesions with overexpression of cyclin Dl are less likely to progress to full malignancy. This surprising idea arose in part from the consideration of four separate studies, in which overexpression of CCNDI in tumours appeared to be associated with a less aggressive phenotype or was a favourable prognostic indicator (Betticher et al, 1996;Bringuier et al, 1996;Gillett et al, 1996;Pelosio et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Abnormal expression of CCNDI and RBI in resection margin epithelia of lung cancer patients

Betticher

Heighway²,

Thatcher³

et al. 1997

Br J Cancer

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Summary Tumours develop through the accumulation of genetic alterations associated with a progressive increase of the malignant phenotype. In lung cancer, chronic exposure of bronchial epithelium to carcinogens in cigarette smoke may lead to multiple dysplastic and hyperplastic lesions scattered throughout the tracheobronchial tree. Little is known about the genetic alterations in such lesions. This study was carried out to examine cyclin Dl (CCND1) and retinoblastoma (RB1) gene expression in the bronchial epithelium of patients with lung cancer. Lung tumours and their corresponding tumour-free resection margins from 33 patients who underwent resection of non-small-cell lung cancer (NSCLC) were examined by immunostaining with monoclonal antibodies against cyclin Dl (DCS-6; Novocastra) and pRb (NCL Rb-1; Novocastra). Examination of the resection margins revealed four carcinomas in situ, 19 hyperplasias and ten sections showing apparently normal bronchial epithelium. A control group of patients, without lung tumours and who had never smoked, revealed no or weak cyclin Dl and positive pRb staining within bronchial epithelia. Increased cyclin Dl and diminished pRb expression were found in 76% (n = 25) and 27% (n = 9) of the resection margins respectively, and in 12% (n = 4) both cyclin Dl and pRb expression were altered. In the corresponding tumours, 48% (n = 16) were normal, while altered expression was found for cyclin Dl in 33% (n = 11), pRb in 27% (n = 9) and both in 9% (n = 3) of cases. It appears that altered expression of cyclin Dl and pRb is an early event in NSCLC development in almost half of cases analysed. Further investigations are needed to determine the significance of immunostaining of bronchial specimens in individuals at risk of lung cancer, with the possibility that the observations are of importance in the early diagnosis of NSCLC.Keywords: non-small-cell lung cancer; carcinogenesis; cyclin D1; CCND1; retinoblastoma protein; RB1; carcinoma in situ Lung cancer has become a worldwide problem with a greater than tenfold increase in incidence of reported disease since 1930. Chronic exposure to bronchial irritants appears to lead to epithelial changes, scattered throughout the tracheobronchial tree (Auerbach et al, 1962a(Auerbach et al, ,b, 1975. Patients with lung cancer have a much greater frequency of epithelial hyperplasia in main bronchi (>90%) compared with patients (10%) who have never smoked (Auerbach et al, 1961). The best evidence for an association between carcinoma in situ and invasive carcinoma probably comes from sputum cytology from uranium miners, which showed increasingly abnormal epithelial cells as the patients progressed towards invasive lung tumours (Saccomanno et al, 1974). These results suggest that the whole tracheobronchial tree is affected by carcinogen exposure. Cells with genetic lesions resulting in a growth advantage are likely to replace the epithelium of the whole tracheobronchial tree and, in the case of additional genetic events, may show invasive growth (Thibervill...

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“…The present study however, highlights the need to further evaluate the relationship between cyclin D1 expression and prognosis given that ampli®cation is a poor surrogate for overexpression. The ®ve studies reported to date have failed to reach a consensus: two reported an improved relapse-free and overall survival in the patients with cyclin D1 overexpressing tumours (Gillett et al, 1996;Pelosio et al, 1996), whereas the other studies failed to identify any impact of cyclin D1 expression on survival (McIntosh et al, 1995;Michalides et al, 1996;van Diest et al, 1997). Further studies are therefore required to elucidate the prognostic signi®cance of cyclin D1 and EMS1 overexpression.…”

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confidence: 99%

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival

et al. 1998

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The EMS1 and CCND1 genes at chromosome 11q13 are ampli®ed in about 15% of primary breast cancers but appear to confer dierent phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene ampli®cation (P=0.0061), whereas cyclin D1 mRNA overexpression was not (P=0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P=0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P=0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically signi®cant (P=0.0951). In marked contrast there was a signi®cant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P=0.030). A potential explanation for this dierence was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without eect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age 450 years (P=0.0001), postmenopausal status (P=0.0008), lymph node negativity (P=0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene ampli®ca-tion, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer dierent phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene ampli®cation.

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Clinical significance of cyclin D1 expression in patients with node-positive breast carcinoma treated with adjuvant therapy

Cited by 51 publications

References 26 publications

Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis

Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis

Abnormal expression of CCNDI and RBI in resection margin epithelia of lung cancer patients

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival

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