Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions

Weinstat-Saslow, Debra; Merino, María J.; Manrow, Richard E.; Lawrence, Julia; Bluth, Ray F.; Wittenbel, Karl D.; Simpson, Jean F.; Page, David L.; Steeg, Patricia S.

doi:10.1038/nm1295-1257

Cited by 303 publications

(180 citation statements)

References 18 publications

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“…This study also supports previous reports of deregulated expression and ampli®cation of cyclin D1 in chemically induced skin tumors (Bianchi et al, 1993;Mitsunaga et al, 1995;Robles and Conti, 1995), human tumors (Bartkova et al, 1995a,b;Wang et al, 1996;Weinstat-Saslow et al, 1995) and in rat mammary tumors (Sgambato et al, 1995). Overexpression of cyclin D1 in the mammary glands of transgenic mice leads to hyperplasia and tumor formation (Wang et al, 1994).…”

Section: Discussionsupporting

confidence: 91%

“…Ampli®cation and overexpression of cyclin D1 has been reported in the pathogenesis of several types of cancer, including carcinomas of human breast, and upper aerodigestive tract and head and neck squamous cell carcinomas (Bartkova et al, 1995b;Jiang et al, 1993;Lammie et al, 1991;Weinstat-Saslow et al, 1995). Early overexpression of cyclin D1 was also observed in the SENCAR mouse skin carcinogenesis model (Bianchi et al, 1993;Robles and Conti, 1995).…”

Section: Introductionmentioning

confidence: 97%

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Deregulated expression of cell-cycle proteins during premalignant progression in SENCAR mouse skin

et al. 1998

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It is now evident that several genes encoding regulatory activities that control the mammalian cell cycle, particularly some that control the progression of quiescent cells through G1 and into S phase, are targets for alterations that underlie the development of neoplasms. Here, we made a sequential study of alterations in cell cycle protein expression and complex formation among cyclin, cyclin dependent kinases (CDKs) and CDK inhibitors (CKIs) during premalignant progression in SENCAR mouse skin tumors. Changes in the level of expression were observed in positive (cyclin D1, D2, and E2F family members) and negative regulators (p16 Ink4a , p57 Kip2 ) of the cell cycle. Also, we observed the formation of cyclin/CDK/CKI complexes. The amounts of these proteins and complexes increased substantially at speci®c times during promotion but not during malignant conversion to carcinomas. These data show that deregulation of growth control occurs in benign tumors and that subsequent mutations not involved cell-cycle regulation are probably necessary to induce invasive behavior.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 97%

Deregulated expression of cell-cycle proteins during premalignant progression in SENCAR mouse skin

et al. 1998

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“…Similar results were observed with atypical ductal hyperplasias, which confer an approximate fourfold increase in risk for invasive breast cancer. However, any form of ductal carcinoma in situ (DCIS), which confers an 8 ± 10-fold increase in risk, was characterized by frequent cyclin D mRNA overexpression (Weinstat-Saslow et al, 1995). Similar trends at the protein level were observed by Simpson et al (submitted for publication).…”

Section: Introductionsupporting

confidence: 60%

Inhibition of cyclin D expression in human breast carcinoma cells by retinoids in vitro

1997

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Transfection and transgenic mouse experiments supported an oncogenic role for cyclin D1 in breast cancer. We recently reported that noninvasive carcinoma in situ lesions of the human breast overexpress cyclin D, suggesting that this molecular event may represent a valuable target for chemoprevention. The purpose of the present series of investigations was to identify agents which could reduce the cyclin D expression of breast cells. We report that 9-cis retinoic acid (9-cis RA) and all trans retinoic acid (tRA) inhibited the cyclin D1 and D3 expression levels of human MCF-7, ZR-75 and T-47D breast carcinoma cells in vitro. Where detectable, similar trends were observed in the immortalized, HBL-100 and MCF-10A breast cell lines. Cyclin D2 was undetectable. The e ect of retinoids was both dose-and time-dependent, and correlated with altered cell cycle kinetics and proliferative status. Retinoids were also found to inhibit the expression levels of other cell cycle related proteins, including Cdk2 and Cdk4, resulting in lower kinase activities. In contrast to other breast prevention studies, no synergistic e ect was observed with retinoids and tamoxifen. The data indicate that retinoids can potently reduce cyclin D expression levels in a variety of breast cell lines in vitro, and suggest further consideration of this mechanism for the chemoprevention of breast cancer.

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“…Normal and hyperproliferative skin were negative for cyclin Dl, and the intensity of cyclin D1 staining was associated with the grade of dysplasia. Another study (Weinstat-Saslow et al, 1995) reports on a large number of human breast biopsies, in which cyclin DI overexpression was found in 87% of ductal carcinoma in situ and in 83% of invasive breast carcinoma lesions, but rarely in normal tissue.…”

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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Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions

Cited by 303 publications

References 18 publications

Deregulated expression of cell-cycle proteins during premalignant progression in SENCAR mouse skin

Deregulated expression of cell-cycle proteins during premalignant progression in SENCAR mouse skin

Inhibition of cyclin D expression in human breast carcinoma cells by retinoids in vitro

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

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