Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein

Nielsen, Niels Hilmer; Emdin, Stefan O.; Cajander, Jenny; Landberg, Göran

doi:10.1038/sj.onc.1200833

Cited by 136 publications

(123 citation statements)

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“…The frequencies of CCND1 amplification (11.2%) and overexpression (33.6%) are in agreement with those previously reported in the literature (Ali et al, 1989;Borg et al, 1991;Schuuring et al, 1992;Henry et al, 1993;McIntosh et al, 1995;Gillett et al, 1996;Barbareschi et al, 1997;Jares et al, 1997;Nielsen et al, 1997;Kenny et al, 1999). Joint analysis of the CCND1 gene at both the mRNA and DNA levels showed that patients with a good outcome had CCND1-unamplified-overexpressed tumours while those with a poor outcome had CCND1-amplified tumours.…”

Section: Discussionsupporting

confidence: 89%

“…Clinical studies have found amplification of 11q13 chromosomal region (which contains CCND1) in 10 -15% of human primary breast cancers (Ali et al, 1989;Borg et al, 1991;Schuuring et al, 1992;Henry et al, 1993). However, overexpression (at both the mRNA and protein levels) is seen in about 50% of cases, suggesting that mechanisms other than DNA amplification may dysregulate cyclin D1 expression (McIntosh et al, 1995;Gillett et al, 1996;Barbareschi et al, 1997;Jares et al, 1997;Nielsen et al, 1997;Kenny et al, 1999). It is noteworthy that it has been previously described a high correlation between overexpression of CCND1 mRNA and increased presence of Cyclin D1 protein (Bartkova et al, 1994;Gillett et al, 1994).…”

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confidence: 99%

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Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays

et al. 2002

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The CCND1 gene, a key cell-cycle regulator, is often altered in breast cancer, but the mechanisms underlying CCND1 dysregulation and the clinical significance of CCND1 status are unclear. We used real-time quantitative PCR and RT -PCR assays based on fluorescent TaqMan methodology to quantify CCND1 gene amplification and expression in a large series of breast tumours. CCND1 overexpression was observed in 44 (32.8%) of 134 breast tumour RNAs, ranging from 3.3 to 43.7 times the level in normal breast tissues, and correlated significantly with positive oestrogen receptor status (P=0.0003). CCND1 overexpression requires oestrogen receptor integrity and is exacerbated by amplification at 11q13 (the site of the CCND1 gene), owing to an additional gene dosage effect. Our results challenge CCND1 gene as the main 11q13 amplicon selector. The relapse-free survival time of patients with CCND1-amplified tumours was shorter than that of patients without CCND1 alterations, while that of patients with CCND1-unamplified-overexpressed tumours was longer (P=0.011). Only the good prognostic significance of CCND1-unamplified-overexpression status persisted in Cox multivariate regression analysis. This study confirms that CCND1 is an ER-responsive or ER-coactivator gene in breast cancer, and points to the CCND1 gene as a putative molecular marker predictive of hormone responsiveness in breast cancer. Moreover, CCND1 amplification status dichotomizes the CCND1-overexpressing tumors into two groups with opposite outcomes.

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays

et al. 2002

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“…In this study, we have shown that low levels of cyclin D1 and p27 correlated to poor prognosis in conventional RCC using univariate analysis, and that p27 remained significantly associated to survival in the multivariate analyses. The association between low cyclin D1 and poor prognosis in the univariate analysis agrees with the data reported for breast cancer (Gillet et al, 1996;Nielsen et al, 1997;Hwang et al, 2002;McKay et al, 2002), although an association between high cyclin D1 and poor prognosis has been reported in many malignancies (Å kervall et al, 1997;Gansauge et al, 1997).…”

Section: Discussionsupporting

confidence: 87%

Expression of cyclin D1, D3, E, and p27 in human renal cell carcinoma analysed by tissue microarray

et al. 2003

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Aberrations in the G1/S transition of the cell cycle have been observed in many malignancies and seem to be critical in the transformation process. Few studies have delineated the presence of G1/S regulatory defects and their clinical relevance in renal cell carcinoma (RCC). Therefore, we have examined the protein contents of cyclin D1, D3, E, and p27 in 218 RCCs, using tissue microarray and immunohistochemistry. The results from a subset of tumours were confirmed by Western blotting and immunohistochemical staining of regular tissue sections. Interestingly, low protein contents of cyclin D1 and p27 were associated with high nuclear grade, large tumour size, and poor prognosis for patients with conventional tumours. We further observed substantial differences in the pattern of G1/S regulatory defects between the different RCC subtypes. The majority of both conventional and papillary cases expressed p27; however, chromophobe tumours generally lacked p27 staining. In addition, conventional RCCs often expressed high cyclin D1 protein levels, while papillary RCCs exhibited high cyclin E. In summary, we have shown that G1/S regulatory defects are present in RCC and are associated with clinico-pathological parameters. The pattern of cell cycle regulatory defects also differed between RCC subtypes.

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“…Barbareschi et al (22) reported on the expression of pRB, cyclin D1 and p53, but not p16, in 64 breast cancers. Dublin et al (15) and Nielsen et al (38) studied breast tumors (n ϭ 192 and n ϭ 114, respectively) for pRB, cyclin D1 and p16, but not p53 expression. Thus, we believe our series of 77 breast cancers to be the first for which immunohistochemical data on all four major cell cycle regulatory proteins (pRB, p16, cyclin D1, and p53) are available.…”

Section: Discussionmentioning

confidence: 99%

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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Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein

Cited by 136 publications

References 41 publications

Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays

Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays

Expression of cyclin D1, D3, E, and p27 in human renal cell carcinoma analysed by tissue microarray

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

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