Expression and amplification of cyclin D1 in primary breast carcinomas: Relationship with histopathological types and clinico-pathological parameters

Naidu, Rakesh; Wahab, Norhanom Abdul; Yadav, Man Mohan; Kutty, Methil Kannan

doi:10.3892/or.9.2.409

Cited by 32 publications

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“…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%

“…[7][8][9][10]13,14,16,17 Conflicting data on the associations between CCND1 amplification and clinicopathological variables and clinical outcome have been reported: while some have found an association between CCND1 amplification and positivity for oestrogen receptor (ER), 7,12,17 lobular histology 7 and poor outcome, 7,8,16 others have failed to find some of these. 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).…”

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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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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: Discussionmentioning

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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“…CCND1 amplifications were found associated with estrogen receptor (ER) and progesterone receptor (PR) positivity (27,29) as well as lobular histologic subtype (29). Studies on the prognostic significance have provided conflicting data including reports associating CCND1 amplification with good prognosis (27) and studies linking CCND1 amplifications with poor prognosis (26,28). The MDM2 gene is located at 12q15.…”

Section: Introductionmentioning

confidence: 99%

“…CCND1 has been mapped to 11q13 and codes for a G 1 -cyclin protein, which controls cell cycle progression during G 1 phase. CCND1 has been found amplified in 10 to 27% of breast cancers (27,28). CCND1 amplifications were found associated with estrogen receptor (ER) and progesterone receptor (PR) positivity (27,29) as well as lobular histologic subtype (29).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Relevance of Gene Amplifications and Coamplifications in Breast Cancer

et al. 2004

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Multiple different oncogenes have been described previously to be amplified in breast cancer including HER2, EGFR, MYC, CCND1, and MDM2. Gene amplification results in oncogene overexpression but may also serve as an indicator of genomic instability. As such, presence of one or several gene amplifications may have prognostic significance. To assess the prognostic importance of amplifications and coamplifications of HER2, EGFR, MYC, CCND1, and MDM2 in breast cancer, we analyzed a breast cancer tissue microarray containing samples from 2197 cancers with follow-up information. Fluorescence in situ hybridizations revealed amplifications of CCND1 in 20.1%, HER2 in 17.3%, MDM2 in 5.7%, MYC in 5.3%, and EGFR in 0.8% of the tumors. All gene amplifications were significantly associated with high grade. HER2 (P < 0.001) and MYC amplification (P < 0.001) were also linked to shortened survival. In case of HER2, this was independent of grade, pT, and pN categories. MYC amplification was almost 3 times more frequent in medullary cancer (15.9%), than in the histologic subtype with the second highest frequency (ductal; 5.6%; P ‫؍‬ 0.0046). HER2 and MYC amplification were associated with estrogen receptor/progesterone receptor negativity (P < 0.001) whereas CCND1 amplification was linked to estrogen receptor/progesterone receptor positivity (P < 0.001). Coamplifications were more prevalent than expected based on the individual frequencies. Coamplifications of one or several other oncogenes occurred in 29.6% of CCND1, 43% of HER2, 55.7% of MDM2, 65% of MYC, and 72.8% of EGFR-amplified cancers. HER2/MYC-coamplified cancers had a worse prognosis than tumors with only one of these amplifications. Furthermore, a gradual decrease of survival was observed with increasing number of amplifications. In conclusion, these data support a major prognostic impact of genomic instability as determined by a broad gene amplification survey in breast cancer.

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“…Cyclin D1 gene amplification in sporadic tumours as well as cyclin D1 RNA expression in ERa positive breast cancer has been correlated to poor prognosis (Kenny et al, 1999;Bieche et al, 2002;Naidu et al, 2002). When studying protein levels, cyclin D1 overexpression has in contrast been associated with better outcome (Gillett et al, 1996;Hwang et al, 2003).…”

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Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients

et al. 2004

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Antioestrogen treatment by tamoxifen is a well-established adjuvant therapy for oestrogen receptor-alpha (ERa) positive breast cancer. Despite ERa expression some tumours do not respond to tamoxifen and we therefore delineated the potential link between the cell cycle regulator and ERa co-factor, cyclin D1, and tamoxifen response in a material of 167 postmenopausal breast cancers arranged in a tissue array. The patients had been randomised to 2 years of tamoxifen treatment or no treatment and the median follow-up time was 18 years. Interestingly in the 55 strongly ERa positive samples with moderate or low cyclin D1 levels, patients responded to tamoxifen treatment whereas the 46 patients with highly ERa positive and cyclin D1 overexpressing tumours did not show any difference in survival between tamoxifen and no treatment. Survival in untreated patients with cyclin D1 high tumours was slightly better than for patients with cyclin D1 low/moderate tumours. However, there was a clearly increased risk of death in the cyclin D1 high group compared to an age-matched control population. Our results suggest that cyclin D1 overexpression predicts for tamoxifen treatment resistance in breast cancer, which is line with recent experimental data using breast cancer cell lines and overexpression systems.

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Expression and amplification of cyclin D1 in primary breast carcinomas: Relationship with histopathological types and clinico-pathological parameters

Cited by 32 publications

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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

Prognostic Relevance of Gene Amplifications and Coamplifications in Breast Cancer

Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients

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