Cyclin D1

Parathyroid Adenomatosis 1 (PRAD1)
BCL-1, Bcl-1
CCND1 (gene locus)

Gene: CCND1 maps to 11q13. The gene spans about 15 kb and has 5 exons; its promoter region has Sp1 binding sites and no obvious TATA box, characteristics of housekeeping genes and growth-regulating genes. Furthermore, an E2F binding motif present close to the major transcription start site may be involved in cell cycle-dependent expression of this gene (Motokura T. and Arnold A., 1993).
mRNA: size: ? kb.
Protein: a 295-amino acids, 34-kDa cyclin. Cyclins are a family of key regulatory proteins that drive the ordered progression of mammalian cells through critical transition points in the cell division cycle. The D-type cyclins control the passage of cells through the G₁ phase, ultimately allowing entry into S phase.
In experiments using mice lacking cyclin D1, embryos developed to term but showed reduced body size, reduced viability, a striking reduction in cell number in their retinas, and symptoms of neurologic impairment. In adult mutant females, the breast epithelial compartment failed to undergo the massive proliferative changes associated with pregnancy despite normal levels of ovarian steroid hormones. Thus, the steroid-induced proliferation of mammary epithelium during pregnancy might be driven through cyclin D1 (Sicinski P. et al., 1995).
In colon carcinoma cells, it has been shown that beta-catenin regulates expression of cyclin D1 (Tetsu O. and McCormick F., 1999).

Cell lines:
- EMS1 and CCND1 genes both map to 11q13. They were found to be co-amplified in MDA-MB-134, -175, -453, and ZR-75-1, whilst 4 BCC lines showed amplification of one gene alone: MDA-MB-157 and MCF-7 (EMS1, see Campbell D.H. et al., 1996) and MDA-MB-330 and -361 (CCND1) (Buckley M.F. et al., 1993).

- Cyclin D1 induction in BCC shortens the G₁-phase of the cell cycle and is sufficient for cells arrested in G₁ to complete the cycle (Musgrove E.A. et al., 1994).

- Estrogens induce cyclin D1 expression in BCC lines (Prall O.W.J. et al., 1997). Whether overexpression of cyclin D1 in BCC may reverse the growth-inhibitory effect of antiestrogens remains controversial (Wilcken N.R.C. et al., 1997; Pacilio C. et al., 1998).

- Cyclin D1 may stimulate ER transcriptional activity (Zwijsen R.M.L. et al., 1997).

- In MCF-7 BCC, estrogen induction of cyclin D1 could involve the interaction between ATF-2/c-Jun heterodimers and a potential cAMP response element (CRE-D1) present in a region between -96 and -29 in the cyclin D1 promoter (Sabbah M. et al., 1999).

- Flavopiridol is a flavonoid that induces cell cycle arrest at different stages of the cell cycle because of the inhibition of cyclin-dependent kinases (cdks). Along with this inhibition, flavopiridol was found to decrease total cyclin-D protein levels in MCF-7 BCC. This decline in cyclin D1 appears to be an early event, specific and, at least in part, due to the transcriptional repression of the cyclin D1 promoter (Carlson B. et al., 1999).

- Several mechanisms leading to overexpression of cyclin D1 in BCC have been reported including amplification, translocation and stabilization of the mRNA. Elevated cyclin D1 protein in breast cancer samples in the absence of elevated mRNA level was also observed. In these cases, it was found that cyclin D3 protein also accumulated and that the coordinate increase in cyclin D1 and D3 occured in 15% (7/47) of breast cancers. In addition, blocking the activity of the 26S proteosome resulted in the accumulation of cyclin D1 and D3, and both D-type cyclins were ubiquitinated and associated with Cul-1, a component of the SCF ubiquitin ligase complex. The coordinated elevation of cyclin D1 and D3 was also observed in MCF-7 BCC and demonstrated that the degradation of cyclin D1 and D3 was deficient in this cell line. These results indicate that cyclin D1 and cyclin D3 share a common mechanism of degradation, suggesting that the coordinate increase of D-type cyclins observed in primary breast cancers reflects a defect in their proteolysis (Russell A. et al., 1999).

- Cyclin D1-overexpressing MCF7 cells appeared more sensitive to ionizing radiation than the nonoverexpressing counterparts. The cyclin D1-overexpressing cells also exhibited a higher induction of apoptosis. Treatment with a dose of 5 Gy resulted in a rapid increase of p53 and p21 in the cyclin D1-overexpressing cells. Nonoverexpressing cells showed a more transient expression of these proteins after ionizing radiation. A pronounced G2-M block was observed in both cell lines. The cyclin D1-overexpressing cells were, however, released earlier from the block than the control cells (Coco Martin J.M. et al., 1999).

Tumors:
- Whereas the 11q13 region is amplified in approximately 13% of breast cancers (Fantl V. et al., 1993), the frequency of cyclin D1 mRNA and protein overexpression is at least 3-fold higher, indicating that the latter may result from mechanisms other than gene amplification (Kenny F.S. et al., 1999).

- In transgenic mice containing the MMTV-LTR (mouse mammary tumor virus long terminal repeat) as a promoter sequence upstream of cyclin D1, overexpression of the transgene resulted in abnormal proliferation of mammary cells and the development of mammary adenocarcinomas (Wang T.C. et al., 1994).

- A strong positive correlation was observed between cyclin D1 mRNA and ER mRNA levels (P=0.0001) in a series of 364 primary breast cancers (Hui R. et al., 1996).

- A series of 1,171 breast tumors were tested for DNA amplification by Southern blotting and a subset of 132 breast cancers were analyzed for RNA expression levels by slot-blot and Northern blotting. Cyclin D1 was found to be activated in a sizeable fraction of the tumors (amplification 12.6%, overexpression 19%). Amplification of cyclin D1 correlated with ER+ breast cancer and the presence of lymph-node metastasis. An association of cyclin D1 expression with invasive lobular carcinoma was found (Courjal F. et al., 1996).

- Positive cyclin D1 expression was found to be associated with increased progression-free survival in male breast carcinoma patients, which suggests that interactions among cell cycle regulatory proteins may be important in this disease (Rayson D. et al., 1998).

- CCND1 expression was analyzed in human mammary carcinomas by immunohistochemical (IHC) and flow-cytometry (FCM) methods: 52.5% and 50% of cases were strong expressors of CCND1 by IHC and FCM analysis respectively. The percentage of CCND1-positive cells was especially high in node-negative (N-) estrogen-receptor-positive (ER+) tumors, probably as a consequence of CCND1 induction by estrogens in steroid-responsive tissues. However, CCNDD1 expression was not related to ER positivity in node-positive tumors (N+) (Collecchi P. et al., 1999).

- In a series of 253 primary breast cancer, cyclin D1 mRNA was positively correlated with ER (P=0.0001), but not associated with age, menopausal status, axillary lymph node status, vascular invasion, tumor size, type, and grade. However, in patients with ER-positive tumors (n=182), high levels of cyclin D1 mRNA were associated with increased risk of relapse (P=0.0016), local recurrence (P=0.025), metastasis (P=0.019), and death (P=0.025). In contrast, there were no clinical correlation with cyclin D1 expression in ER-negative disease (n=71) (Kenny F.S. et al., 1999).

- Concurrent deregulation of gelsolin and cyclin D1 was found to be highly prevalent among breast cancers of humans and rodents, with both defects present in 89% of the neoplasms analyzed (Dong Y. et al., 1999).

Buckley M.F. et al. (1993) Expression and amplification of cyclin genes in human breast cancer. Oncogene 8, 2127-2133.
Campbell D.H. et al. (1996) Expression and tyrosine phosphorylation of EMS1 in human breast cancer cell lines. Int. J. Cancer 68, 485-492.
Carlson B. et al. (1999) Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res. 59, 4634-4641.
Coco Martin J.M. et al. (1999) Cyclin D1 overexpression enhances radiation-induced apoptosis and radiosensitivity in a breast tumor cell line. Cancer Res. 59, 1134-1140.
Collecchi P. et al. (1999) Cyclin-D1 expression in node-positive (N+) and node-negative (N-) infiltrating human mammary carcinomas. Int. J. Cancer 84, 139-144.
Courjal F. et al. (1996) Cyclin gene amplification and overexpression in breast and ovarian cancers: evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors. Int. J. Cancer 69, 247-253.
Dong Y. et al. (1999) Concurrent deregulation of gelsolin and cyclin D1 in the majority of human and rodent breast cancers. Int. J. Cancer 81, 930-938.
Fantl V. et al. (1993) Chromosome 11q13 abnormalities in human breast cancer. Cancer Surv. 18, 77-94.
Hinds P.W. et al. (1994) Function of a human cyclin gene as an oncogene. Proc. Nat. Acad. Sci. USA 91, 709-713.
Hui R. et al. (1996) Cyclin D1 and estrogen receptor mRNA expression are poitively correlated in primary breast cancer. Clin Cancer Res. 2, 923-928.
Inaba T. et al. (1992) Genomic organization, chromosomal localization, and independent expression of human cyclin D genes. Genomics 13, 565-574.
Kenny F.S. et al. (1999) Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer. Clin. Cancer Res. 5, 2069-2076.
Komatsu H. et al. (1994) A variant chromosome translocation at 11q13 identifying PRAD1/cyclin D1 as the BCL-1 gene. Blood 84, 1226-1231.
Motokura T. et al. (1991) A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350, 512-515.
Motokura T. and Arnold A. (1993) PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint. Genes Chromosomes Cancer 7, 89-95.
Musgrove E.A. et al. (1994) Cyclin D1 induction in breast cancer cells shortens G₁ and is sufficient for cells arrested in G₁ to complete the cell cycle. Proc. Natl. Acad. Sci. USA 91, 8022-8026.
Pacilio C. et al. (1998) Constitutive overexpression of cyclin D1 does not prevent inhibition of hormone-responsive human breast cancer cell growth by antiestrogens. Cancer Res. 58, 871-876.
Prall O.W.J. et al. (1997) Estrogen-induced activation of cdk4 and cdk2 during G₁-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-cdk2. J. Biol. Chem. 272, 10882-10894.
Rayson D. et al. (1998) Molecular markers in male breast carcinoma. Cancer 83, 1947-1955.
Russell A. et al. (1999) Cyclin D1 and D3 associate with the SCF complex and are coordinately elevated in breast cancer. Oncogene 18, 1983-1991.
Sabbah M. et al. (1999) Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proc. Natl. Aced. Sci. USA 96, 11217-11222.
Sicinski P. et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82, 621-630.
Tetsu O. and McCormick F. (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422-426.
Wang T.C. et al. (1994) Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369, 669-671.
Wilcken N.R.C. et al. (1997) Inducible overexpression of cyclin D1 in breast cancer cells reverse the growth-inhibitory effect of antiestrogens. Clin. Cancer Res. 3, 849-854.
Zwijsen R.M.L. et al. (1997) Cdk-independent activation of estrogen receptor by cyclin D1. Cell 88, 405-415.
Xiong Y. et al. (1991) Human D-type cyclin. Cell 65, 691-699.