Cyclin D1 amplification and expression in human breast carcinoma: correlation with histological prognostic markers and oestrogen receptor expression

Worsley, Sally; Jennings, Barbara; Khalil, Khesar Hussein; Mole, M.; Girling, Anne

doi:10.1136/mp.49.1.m46

Cited by 20 publications

(30 citation statements)

References 8 publications

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“…cyclin Dl accumuiaiion, as detected immunohistochemically, has been observed in up to 81% of cases and gene amplification has been observed in between 11 and 23% of cases (Zhang et al. 1994, Frierson et al, 1996, Lammie et al, 1991, Worsley et al, 1996. In the present study cyclin Dl gene amplification and protein overexpression were detected in breast tissues at similar frequencies to those reported by others.…”

Section: Discussionsupporting

confidence: 76%

“…The lack of correlation between cyclin Dl gene amplification and protein overexpression has been described previously (Frierson et al, 1996, Simpson et al, 1997, Worsley et al, 1996, Pelosio et al, 1996. It has been suggested that mechanisms other than gene amplification, such as post-transcnptional or post-translational mechanisms, could cause increased levels of cyclin Dl protein (Simpson et al, 1997, Worsley et al, 1996. For example, accumulation of cyclin Dl protein ca~ occur because of transactivation of the cyclin Dl promoter by ß-catenin (Lin et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Cohert Study of the Relationship Between c-erbB-2 and Cyclin D1 Overexpression, p53 Mutation and/or Protein Accumulation, and Risk of Progression from Benign Breast Disease to Breast Cancer; and Creation of a Bank of Benign Breast Tissue

Kandel¹

2000

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REPORT DOCUMENTATION PAGEForm Publk>reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Paperwork Reduction Project 10704-0188), Washington, DC 20503 AGENCY USE ONLY (Leave blank) REPORT DATE October 2000 REPORT TYPE AND DATES COVERED Annual(13Sep99-lSep00) AUTHOR(S)Rita A. Kandel, M.D. FUNDING NUMBERS DAMD17-96-1-6179 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Mount Sinai Hospital Toronto, Ontario Canada M5G 1X5 E-MAIL:rkandel@mtsinai. on. ca In a case control study, nested within a cohort of 4,888 women with benign breast disease, we demonstrated that p53 protein accumulation detected by immunohistochemistry was associated with a two-fold increase in risk to develop breast cancer. The purpose of this project is: 1) collect paraffin-embedded benign breast tissue from the remaining 4,336 cohort members who were not part of the case-control study. (2) to enlarge the completed case-control study of p53 with an additional 63 cases (and 5 matched controls per case) and examine the biopsies from these subjects for evidence of c-erbB-2 overexpression and p53 protein accumulation. As well, we will examine the tissue for the presence of p53 mutations in this group and (3) examine whether cyclin Dl amplification and/or protein overexpression is a molecular marker of risk of progression from BBD to breast cancer. The collection of paraffin blocks is ongoing. We have analyzed all the p53 immunopositive breast tissues and 15 subjects whose breast tissue did not show p53 protein accumulation. p53 sequence changes occurred in 59.2% (16/27) of p53 immunopositive tissues and of these 33% (9/27) were p53 mutations. Four (26.7%) of the immunonegative tissues showed gene alterations of which one was a mutation. The existing case-control group was examined for cyclin Dl changes. Twelve cases and 29 controls showed cyclin Dl amplification. After adjustment for confounding there was a statistically non-significant 40% increase in risk of breast cancer in association with cyclin Dl amplification. Cyclin Dl overexpression was seen in 75 samples of benign breast disease (15 cases and 60 controls). The presence of cyclin Dl overexpression was not associated with increased risk of developing breast cancer (unadjusted odds ratio = 1.07, 95% confidence intervals = 0.56-2.03). PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U SUBJECT TERMS Breast Cancer NUMBER OF PAGES 71 PRICE CODE INTRODUCTIONWe have completed a study of ...

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

A Cohert Study of the Relationship Between c-erbB-2 and Cyclin D1 Overexpression, p53 Mutation and/or Protein Accumulation, and Risk of Progression from Benign Breast Disease to Breast Cancer; and Creation of a Bank of Benign Breast Tissue

Kandel¹

2000

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“…Using the same antibody and staining cut-off (5%), our data are very similar to those reported by Bartkova et al (16). Whereas we did not probe for amplification of the gene, it is well documented that gene amplification accounts for less than half of the cases with cyclin D1 overexpression (17)(18)(19). Ductal and lobular carcinomas had similar rates of cyclin D1 overexpression.…”

Section: Discussionmentioning

confidence: 94%

“…Like two other studies (22,23), but unlike a third one (20), we found no association between cyclin D1 status and DNA ploidy. We were not able to study the association between positive estrogen receptor status and cyclin D1 overexpression, as has been documented by a number of other investigators (6,18,21,22).…”

Section: Discussionmentioning

confidence: 95%

Abnormal Expression of Cell Cycle Regulatory Proteins in Ductal and Lobular Carcinomas of the Breast

Geradts

Ingram

2000

Modern Pathology

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In a previous study, we demonstrated that the G1 cell cycle checkpoint in carcinomas of the breast is frequently abrogated by loss of p16, the product of the CDKN2/INK4A gene, and, to a lesser extent, by loss of pRB, the product of the retinoblastoma gene. The purpose of the present study was to determine whether other mechanisms of cell cycle deregulation exist in breast cancers which have retained RB and p16 function. Paraffin sections of 81 invasive breast carcinomas (49 ductal, 26 lobular, 6 mixed) were reacted with monoclonal antibodies against cyclin D1 and p53, using optimized immunohistochemical staining protocols. The staining results were correlated with the expression of p16 and pRB, and with a variety of pathological parameters and DNA ploidy. Twenty-five tumors (31%) accumulated (presumably mutant) p53 and 28 (35%) overexpressed cyclin D1; 7 carcinomas (not including any pure lobular cancers) abnormally expressed both proteins. p53 accumulation correlated with nuclear, mitotic, and overall grade, but not with tumor size, lymph node involvement, or DNA ploidy. Overexpression of cyclin D1 was not associated with any of the patho-biological variables. There was an inverse correlation between loss of p16 and high levels of p53, but not cyclin D1. The G1 cell cycle checkpoint, which is controlled by RB, cyclin D1, and p16, was abrogated in 65% of carcinomas, and only p53 was abnormal in an additional 17%. The number of abnormally expressed genes correlated with mitotic activity and overall tumor grade, but not with tumor histology, size, or nodal status, suggesting that cell cycle deregulation is an early event in breast tumorigenesis. Only 18% of the carcinomas showed a normal level of expression of the four genes tested, and p16 appeared to be the most common target of cell cycle deregulation. These data point to the importance of cell cycle regulatory protein abnormalities in human breast cancer.KEY WORDS: Breast cancer, Cell cycle, Cyclin D1, Immunohistochemistry, p16, p53, Pathology. Mod Pathol 2000;13(9):945-953It is generally accepted that several pathways need to be abrogated in the genesis of a malignant neoplasm. There is an increasing body of evidence that deregulation of one or more of the cell cycle checkpoints is among the most common abnormalities in human neoplasia. We have been particularly interested in the genes controlling the late G1 restriction point. Possibly the most critical component of the latter is pRB, the product of the retinoblastoma gene. Hyperphosphorylation, and hence inactivation of pRB is catalyzed by cyclin dependent kinases (CDKs), most notably CDK4 and 6. The CDKs are activated by binding to their respective cyclins, including cyclin D1 (1). They are inhibited by CDK inhibitors including p15 INK4B and p16 INK4A (specific for CDK4/6) and p21 WAF1 . The latter, in turn, is partially under the transcriptional control of p53 (2). We recently demonstrated that abnormal expression of the genes controlling the G1 restriction point is a very common occurrence in carcinomas ...

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“…NF-kB activity and cyclin D1 overexpression has been linked to multiple cancers [Karin, 2006;Alao, 2007] and clinical studies utilizing breast and head and neck tumor samples have revealed that cyclin D1 overexpression is prevalent in a large percentage of tumors (50-70%). Interestingly, this over expression has been linked to genomic duplication of cyclin D1 in only a subset of these tumors (10-20%) [Masuda et al, 1996;Worsley et al, 1996;Monden et al, 1997;Simpson et al, 1997], leaving the possibility that p65-mediated regulation of cyclin D1 in this disease may occur at the post-translational level.…”

Section: Journal Of Cellular Biochemistry Cyclin D1 Protein Stabilitymentioning

confidence: 99%

The RelA/p65 subunit of NF‐κB specifically regulates cyclin D1 protein stability: Implications for cell cycle withdrawal and skeletal myogenesis

Dahlman

Wang

Bakkar

et al. 2008

J of Cellular Biochemistry

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Studies support that NF-kappaB functions in cellular growth through the transcriptional regulation of cyclin D1, but whether such regulation is attributed to a single NF-kappaB subunit remains unclear. To address this issue we examined endogenous cyclin D1 levels during cell cycle re-entry in mouse embryonic fibroblasts (MEFs) lacking specific NF-kappaB signaling subunits. Results showed that each of these subunits were dispensable for regulating cyclin D1 transcription. However, we found that resulting cyclin D1 protein was severely reduced in MEFs lacking only RelA/p65. Cyclohexamide treatment revealed that this regulation was due to an increase in protein turnover. Similar downregulation of cyclin D1 protein, but not RNA, was observed in vivo in multiple tissues lacking RelA/p65. Co-immunoprecipitation analysis also showed that RelA/p65 and cyclin D1 were capable of interacting, thus providing a possible explanation for cyclin D1 protein stability. In addition, although the decrease in cyclin D1 in RelA/p65(-/-) MEFs was concomitant with lower CDK4 activity during cell cycle re-entry, this was not sufficient to affect S phase progression. Nevertheless, similar decreases in cyclin D1 protein in primary RelA/p65(-/-) myoblasts was adequate to accelerate cell cycle exit and differentiation of these cells. Based on these findings we conclude that RelA/p65 functions as a specific regulator of cyclin D1 protein stability, necessary for proper cell cycle withdrawal during skeletal myogenesis.

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Cyclin D1 amplification and expression in human breast carcinoma: correlation with histological prognostic markers and oestrogen receptor expression

Cited by 20 publications

References 8 publications

A Cohert Study of the Relationship Between c-erbB-2 and Cyclin D1 Overexpression, p53 Mutation and/or Protein Accumulation, and Risk of Progression from Benign Breast Disease to Breast Cancer; and Creation of a Bank of Benign Breast Tissue

A Cohert Study of the Relationship Between c-erbB-2 and Cyclin D1 Overexpression, p53 Mutation and/or Protein Accumulation, and Risk of Progression from Benign Breast Disease to Breast Cancer; and Creation of a Bank of Benign Breast Tissue

Abnormal Expression of Cell Cycle Regulatory Proteins in Ductal and Lobular Carcinomas of the Breast

The RelA/p65 subunit of NF‐κB specifically regulates cyclin D1 protein stability: Implications for cell cycle withdrawal and skeletal myogenesis

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