Specific protection against breast cancers by cyclin D1 ablation

Yu, Qunyan; Geng, Yan; Siciński, Piotr

doi:10.1038/35082500

Cited by 869 publications

(751 citation statements)

References 27 publications

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“…Absence of cyclin D1 in normal MECs results in normal ductal development suggesting that cyclin D1 is dispensable for proliferation of normal MECs. In contrast, cancerous MECs overexpressing ras and neu oncogenes are absolutely dependent on cyclin D1 for malignant transformation (Yu et al, 2001). Similarly, in our study, absence of cyclin D1 in abnormal ERa-overexpressing MECs interrupted cell proliferation and led to apoptosis.…”

Section: Discussionsupporting

confidence: 59%

“…Cyclin D1 knockout mice undergo normal pubertal mammary gland development but they fail to develop lobuloalveolar structures during pregnancy (Fantl et al, 1995;Sicinski et al, 1995). Cyclin D1 appears to play a very specific role in mammary gland development since the lobuloalveolar defect in cyclin D1 knockout mice occurs even in the presence of cyclin D2 and D3 overexpression (Yu et al, 2001). Genetic replacement of cyclin D1 by cyclin D2 can drive nearly normal mammary gland development even during pregnancy (Carthon et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

et al. 2007

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We have previously shown that increased and deregulated estrogen receptor a expression in the mammary gland leads to the development of proliferative disease and cancer. To address the importance of cyclin D1 in ERa-mediated mammary tumorigenesis, we crossed ERa-overexpressing mice with cyclin D1 knockout mice. Mammary gland morphogenesis was completely interrupted in the ERa-overexpressing cyclin D1-deficient triple transgenic mice. In addition to a highly significant reduction in mammary epithelial cell proliferation, cyclin E was upregulated resulting in DNA damage checkpoint activation and apoptosis. This imbalance between proliferative and apoptotic rates in conjunction with remarkable structural defects and cellular disorganization in the terminal end buds interrupted ductal morphogenesis. Interestingly, the structure of the mammary fat pad was fundamentally altered by the consequences of overexpressing ERa in the epithelial cells in the absence of cyclin D1 illustrating how alterations in the epithelial compartment can impact surrounding stromal composition. Transplantation of embryonic ERa-overexpressing and cyclin D1-deficient mammary epithelium into the cleared fat pad of wild-type mice did not rescue the aberrant mammary gland phenotype indicating that it was intrinsic to the mammary epithelial cells. In conclusion, although cyclin D1 is not essential for proliferation of normal mammary epithelial cells, ERa-overexpressing cells are absolutely dependent on cyclin D1 for proliferation. This differential requirement for cyclin D1 in normal vs abnormal mammary epithelial cells supports the application of cyclin D1 inhibitors as therapeutic interventions in ERa-overexpressing breast cancers.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

et al. 2007

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“…33 Moreover, CCND1 deficient mice are resistant to breast cancer induced by ERBB2 and RAS oncogenes. 34 These findings point to a central role of CCND1 in breast cancer pathogenesis and our results suggest that this is true also for MBC.…”

Section: Discussionsupporting

confidence: 74%

Frequent amplification and overexpression of CCND1 in male breast cancer

Bärlund

Kuukasjärvi

Syrjäkoski

et al. 2004

Intl Journal of Cancer

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Genetic events underlying the pathogenesis of breast cancer have been studied extensively and several clinically significant markers have been identified. For example, amplification and overexpression of the ERBB2 oncogene is associated with poor prognosis in breast cancer and ERBB2 serves as a target for antibody-based therapy. Current knowledge on the pathogenesis of male breast cancer (MBC) is limited. The purpose of our study was to investigate the potential relevance of a series of genes known to be amplified in female breast cancer (FBC) in a the development and pathogenesis of MBC. To this end, we applied fluorescence in situ hybridization and immunohistochemistry to the analysis of 128 breast tumors from males. Amplification of ERBB2, MYC, PPM1D and ZNF217 was detected rarely (1-2% of tumors) indicating a considerably lower amplification frequency than in FBC. CCND1 amplification was observed in 12% of cases, being in good concordance with findings from FBC. In addition, CCND1 overexpression was detected in 63% of tumors and was associated with ER positivity (p < 0.0001). Our results indicate distinct differences in the genetic basis of MBC and FBC and suggest that marked differences exist in the pathogenesis of these diseases. The lack of ERBB2 involvement was especially unexpected and implies that ERBB2-targeted therapies are unlikely to be beneficial in MBC. Furthermore, the high frequency of hormone receptor positivity and the association between ER positivity and CCND1 overexpression supports the notion that hormonal regulation is likely to be essential for the development of MBC. © 2004 Wiley-Liss, Inc. Key words: male breast cancer; gene amplification; CCND1; tissue microarrayMale breast cancer (MBC) is a rare disease, representing Ͻ1% of all breast cancers and Ͻ1% of all cancers in men. 1,2 All histological types of breast cancer have been identified in men, with infiltrating ductal carcinoma representing about 80% of cases. Similarly to FBC, hormonal, genetic, and environmental factors are involved in the etiology of MBC. 3 Conditions associated with increased estrogen or decreased androgen levels, such as Klinefelter syndrome and testicular disorders, predispose to MBC. 1 Particularly, the Klinefelter syndrome, characterized by 47,XXY karyotype, is associated with a 50-fold increase in breast cancer risk. 4 The genetic factor most clearly associated with MBC is BRCA2 germline mutation and its frequency in men with breast cancer varies considerably (4 -40%) depending on the population investigated. 3,5 Germline BRCA1 mutations are also found in male breast cancer patients. 5 The possible role and clinical utility of oncogene alterations have been widely investigated in FBC. The most extensively studied is the ERBB2 oncogene that belongs to the epidermal growth factor receptor family. ERBB2 is amplified and overexpressed in 10 -34% of FBC and has been shown to have prognostic and predictive value. 6 Targeted therapy against ERBB2 is currently undergoing clinical trials and shows potential benefit...

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“…52 Moreover, it has been shown recently that cyclin D1 may be the target of c-erb-B2-and Ras-mediated oncogenic pathways. 53 Of note, recent molecular studies suggest that p27 and other CDK inhibitors of Cip/Kip family, in contrast with their inhibitory function for cyclin E-and cyclin A-dependent CDKs, also may act as positive regulators of cyclin D-dependent kinases (reviewed in Sherr and Roberts 54 ). Indeed, it has been shown that cyclin D3-CDK6-p27 and cyclin D1/2-CDK4/6-p27 complexes are enzymatically active.…”

Section: Discussionmentioning

confidence: 99%