Cyclin D1 (PRAD1) has emerged as a major oncogene involved in a variety of human tumors including up to 50 percent of breast cancers. Numerous studies, generally employing in vitro systems, have led to the widely accepted paradigm that cyclin D1 functions in a biochemical pathway with cyclin- dependent kinase (cdk) 4 or 6, which it activates, the pl6 inhibitor of cdk4/6, and the retinoblastoma oncosuppressor protein pRB, thought to be the primary substrate of cyclin D1- activated cdk. These molecules have tremendous significance to cancer, being targeted by mutation or regulatory derangements in most or perhaps even all cancers. Current concepts of cyclin D1 function, however, may not fully reflect its true role when overexpressed in the complex in vivo process of tumorigenesis. Recent data, in fact, indicate that cyclin D1 may contribute to oncogenesis through mechanisms other than, or in addition to, its role in the cdk4/6 - pRB pathway, for example by activating the estrogen receptor in breast cancer cells. Our mammary cancer- prone transgenic mice with targeted overexpression of cyclin D1 constitute an especially relevant system in which to test such hypotheses. The proposed studies are designed to address the mechanisms through which cyclin D1 contributes to breast cancer using the pathophysiologically relevant experimental context of the intact animal. The studies will (a) examine whether overexpressed cyclin D1 may contribute to mammary tumorigenesis through mechanisms apart from activation of cdk4, by developing and characterizing transgenic mice with a mammary-targeted mutant cyclin D1 transgene unable to activate cdk4; (b) examine whether overexpressed cyclin D1 may contribute to mammary tumorigenesis through mechanisms that do not rely on its ability to interact with pRB, by developing and characterizing transgenic mice with a mammary-targeted mutant cyclin D1 transgene unable to interact with pRB; (c) examine whether overexpressed cyclin D1 may significantly contribute to mammary tumorigenesis through direct activation of the estrogen receptor, by developing and characterizing transgenic mice with a mammary-targeted mutant cyclin D1 transgene unable to activate the estrogen receptor. These results will carry important implications to the molecular pathogenesis of breast cancer, and may ultimately contribute to novel treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055909-12
Application #
6732772
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Spalholz, Barbara A
Project Start
1992-02-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
12
Fiscal Year
2004
Total Cost
$290,000
Indirect Cost
Name
University of Connecticut
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Casimiro, Mathew C; Di Sante, Gabriele; Crosariol, Marco et al. (2015) Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis. Oncotarget 6:8525-38
Casimiro, Mathew C; Crosariol, Marco; Loro, Emanuele et al. (2012) ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice. J Clin Invest 122:833-43
Radaelli, E; Arnold, A; Papanikolaou, A et al. (2009) Mammary tumor phenotypes in wild-type aging female FVB/N mice with pituitary prolactinomas. Vet Pathol 46:736-45
Arnold, Andrew; Papanikolaou, Alexandros (2005) Cyclin D1 in breast cancer pathogenesis. J Clin Oncol 23:4215-24
Arnold, Andrew; Shattuck, Trisha M; Mallya, Sanjay M et al. (2002) Molecular pathogenesis of primary hyperparathyroidism. J Bone Miner Res 17 Suppl 2:N30-6
Hosokawa, Y; Papanikolaou, A; Cardiff, R D et al. (2001) In vivo analysis of mammary and non-mammary tumorigenesis in MMTV-cyclin D1 transgenic mice deficient in p53. Transgenic Res 10:471-8
Hosokawa, Y; Arnold, A (1998) Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells: analysis of allele-specific expression. Genes Chromosomes Cancer 22:66-71
Oyama, T; Kashiwabara, K; Yoshimoto, K et al. (1998) Frequent overexpression of the cyclin D1 oncogene in invasive lobular carcinoma of the breast. Cancer Res 58:2876-80
Uchimaru, K; Taniguchi, T; Yoshikawa, M et al. (1997) Detection of cyclin D1 (bcl-1, PRAD1) overexpression by a simple competitive reverse transcription-polymerase chain reaction assay in t(11;14)(q13;q32)-bearing B-cell malignancies and/or mantle cell lymphoma. Blood 89:965-74
Hosokawa, Y; Gadd, M; Smith, A P et al. (1997) Cyclin D1 (PRAD1) alternative transcript b: full-length cDNA cloning and expression in breast cancers. Cancer Lett 113:123-30

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