Cyclin-d1-gene amplification and expression in breast carcinoma: Relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21waf1 immunohistochemical expression

Barbareschi, Mattia; Pelosio, Paola; Caffo, Orazio; Buttitta, Fiamma; Pellegrini, Silvia; Barbazza, Renzo; Palma, Paolo Dalla; Bevilacqua, Generoso; Marchetti, Antonio

doi:10.1002/(sici)1097-0215(19970422)74:2<171::aid-ijc5>3.0.co;2-w

Cited by 67 publications

(54 citation statements)

References 12 publications

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“…Our findings largely coincide with those of Michalides et al (21), who studied 243 breast cancers and Barbareschi et al (22), who reported on 64 tumors. Like both of these groups, we found no correlation between cyclin D1 and p53 abnormalities in the whole cohort.…”

Section: Discussionsupporting

confidence: 92%

“…Our data support the concept that persistent elevation of intranuclear cyclin D1 occurs early in mammary neoplasia and is maintained during tumor progression (17). 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: Discussionsupporting

confidence: 87%

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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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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 87%

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

Geradts

Ingram

2000

Modern Pathology

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“…It should also be mentioned that cyclin D1 is stimulating OR transcriptional activity only when it is free of its regular cdk4/6 partner (Zwijsen et al, 1997), but that free cyclin D1 is more prone to proteolytic degradation than when bound to cdk4/6 (Diehl et al, 1997). Another confounding factor may be the activation by cyclin D1 of p21 (Barbareschi et al, 1997;De Jong et al, 1999). We applied the immunohistological stainings of cell cycle related markers on the residual samples available from the original IKA Tamoxifen study of 1662 patients.…”

Section: Discussionmentioning

confidence: 99%

Cyclin A is a prognostic indicator in early stage breast cancer with and without tamoxifen treatment

et al. 2002

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Overexpression of G1-S regulators cyclin D1 or cyclin A is frequently observed in breast cancer and is also to result in ligandindependent activation of oestrogen receptor in vitro. This might therefore, provide a mechanism for failure of tamoxifen treatment. We examined by immunohistochemical staining the effect of deregulation of these, and other cell cycle regulators on tamoxifen treatment in a group of 394 patients with early stage breast cancer. In univariate analysis, expression of cyclin A, Neu, Ki-67 index, and lack of OR expression were significantly associated with worse prognosis. When adjusted by the clinical model (for lymph node status, age, performance status, T-classification, grade, prior surgery, oestrogen receptor status and tamoxifen use), only overexpression of cyclin A and Neu were significantly associated with worse prognosis with hazard ratios of, respectively, 1.709 (P=0.0195) and 1.884 (P=0.0151). Overexpression of cyclin A was found in 86 out of the 201 ORpositive cases treated with tamoxifen, and was the only independent marker associated with worse prognosis (hazard ratio 2.024, P=0.0462). In conclusion, cyclin A is an independent predictor of recurrence of early stage breast cancer and is as such a marker for response in patients treated with tamoxifen.

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“…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).…”

mentioning

confidence: 99%

“…Experimental data show that cyclin D1 expression can be regulated by several factors which may be dysregulated in breast cancer, including growth factors (Musgrove et al, 1993), p53 through p21WAF1 (Chen et al, 1995) and oestrogen (Musgrove et al, 1994;Altucci et al, 1996). It is noteworthy that most CCND1-overexpressing tumours are oestrogen receptor-positive (Hui et al, 1996;Barbareschi et al, 1997;Jares et al, 1997). Finally, cyclin D1 is frequently overexpressed in ductal carcinoma in situ, and also in some benign breast diseases (Weinstat-Saslow et al, 1995;Alle et al, 1998), pointing to a role in the earliest stages of breast tumour development.…”

mentioning

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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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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Cyclin-d1-gene amplification and expression in breast carcinoma: Relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21waf1 immunohistochemical expression

Cited by 67 publications

References 12 publications

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

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

Cyclin A is a prognostic indicator in early stage breast cancer with and without tamoxifen treatment

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

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