REVIEWCyclin D1 and breast cancer
Introduction
Cyclin D1 is the product of the CCND1 (PRAD1) gene located on chromosome 11q13 and is amplified in some 15% of breast cancers.1, 2 However, cyclin D1 is overexpressed at the mRNA and protein level in over 50% of the breast cancers in the presence or absence of gene amplification2, 3 and qualifies as one of the most commonly overexpressed proteins in breast cancer.
The stimulation of growth-arrested cells in response to various oncogenes such as ras, myc, E1A4, 5, 6 and mitogenic growth factors such as members of EGF, IGF families result in the induction of the D-type cyclins.7 These cyclins link the extracellular signals to the cell-cycle machinery8 and of the three D-type cyclins, it is cyclin D1 that is predominantly associated with human tumorigenesis.9
Section snippets
Normal cell cycle
The p16–cyclinD1–CDK4 (cyclin-dependent kinase 4)–Rb pathway is central to the regulation of the G1–S phase transition in the cell cycle (Fig. 1) and alteration or mutation of one of the components of this pathway is encountered in most human cancers, the most prominent being cyclin D1.10, 11, 12 G1 cyclins (cyclins D and E) control the progression through the restriction point during late-G1 phase when cells lose their dependency on mitogens and commit to DNA synthesis.13
Class D cyclins (D1,
Non-cell cycle associated CDK-independent function of cyclin D1 (cyclin D1 as a transcriptional regulator)
Cyclin D1 can regulate the growth of oestrogen-responsive tissues by activating the oestrogen receptor (ER) in a ligand-independent fashion, i.e. in the absence of oestrogen.30 Cyclin D1 binds to the hormone-binding domain of ER and promotes association between ER and one of its coactivators resulting in upregulation of ER-mediated transcription through a CDK-independent mechanism.30, 31 This oestrogen-independent ER-agonistic activity of cyclin D1 could underlie its oncogenic role in
Cyclin D1 and oestrogen
The mitogenic effects of oestradiol (E2) are mediated by at least two E2 target genes, c-myc39 and cyclin D1,29, 40, 41 each working independently.27 Of the two regulatory genes, myc is activated earlier by E2 than cyclin D1 in the G1 phase.42 These pathways converge at the activation of cyclin E–CDK2 complexes (Fig. 3). The active cyclin E–CDK2 complexes are depleted of the CDKI p21cip1 being sequestered by cyclin D1.20 Phosphorylation of pRB (retinoblastoma) follows in response to activation
Cyclin D1 and breast cancer
Cyclin D1 overexpression has been reported between 40 and 90% of cases of invasive breast cancer, while gene amplification is seen in about 5–20% of tumours.2, 56, 60, 68 Though CCND1 amplification correlates well with the overexpression of the protein,69, 70 high expression of cyclin D1 is not always secondary to gene amplification implying that other mechanisms contribute to maintain cyclin D1 overexpression. Various factors that could contribute to protein overexpression in breast cancer
Conclusions
CCND1 is an oestrogen-responsive gene and carries an oncogenic potential by actions influencing cell-cycle regulation at the G1/S phase transition and transcriptional regulation. Its product, cyclin D1 is overexpressed in more than half of invasive breast cancers. Recent evidence suggests that cyclin D1 interferes with the effect of tamoxifen and ER-positive breast cancers with cyclin D1 overexpression could potentially account for treatment failure while on tamoxifen therapy. The current data
References (94)
Mammalian G1 cyclins
Cell
(1993)- et al.
CDK-independent activation of estrogen receptor by cyclin D1
Cell
(1997) Linking cyclins to transcriptional control
Gene
(2002)- et al.
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
(1997) - et al.
Estrogens and cell-cycle regulation in breast cancer
Trends Endocrinol Metab
(2001) - et al.
Cyclin D1 provides a link between development and oncogenesis in the retina and breast
Cell
(1995) - et al.
Rescue of cyclin D1 deficiency by knockin cyclin E
Cell
(1999) - et al.
The activities of cyclin D1 that drive tumorigenesis
Trends Mol Med
(2004) - et al.
Cyclin D1 in breast premalignancy and early breast cancer: implications for prevention and treatment
Cancer Lett
(2001) - et al.
Novel, potent and selective cyclin D1/cdk4 inhibitors: indolo[6,7-a]pyrrolo[3,4-c]carbazoles
Bioorg Med Chem Lett
(2003)
Cyclin D1, EMS1 and 11q13 amplification in breast cancer
Breast Cancer Res Treat
Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining
Cancer Res
Expression and amplification of cyclin genes in human breast cancer
Oncogene
Oncogenic activity of cyclin D1 revealed through cooperation with Ha-ras: link between cell cycle control and malignant transformation
Oncogene
Function of a human cyclin gene as an oncogene
Proc Natl Acad Sci USA
Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice
EMBO J
Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression
Mol Cell Biol
Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells: analysis of allele-specific expression
Genes Chromosomes Cancer
A novel cyclin encoded by a bcl1-linked candidate oncogene
Nature
Amplification and expression of the human cyclin D gene in esophageal cancer
Cancer Res
Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas
Oncogene
G1 events and regulation of cell proliferation
Science
D-type cyclin-dependent kinase activity in mammalian cells
Mol Cell Biol
The regulation of E2F by pRB-family proteins
Genes Dev
The consensus motif for phosphorylation by cyclin D1–cdk4 is different from that for phosphorylation by cyclin A/E–cdk2
EMBO J
Cyclins and breast cancer
J Mammary Gland Biol Neoplasia
CDK inhibitors: positive and negative regulators of G1-phase progression
Genes Dev
A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4
Nature
Mammalian G1 cyclins and cell cycle progression
Proc Assoc Am Physicians
Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression
Oncogene
Antisense to cyclin D1 inhibits growth and reverses the transformed phenotype of human esophageal cancer cells
Oncogene
Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice
Nature
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
Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts
Genes Dev
Cyclin D1 is a nuclear protein required for cell cycle progression in G1
Genes Dev
c-Myc or cyclin D1 mimics estrogen effects on cyclin E–cdk2 activation and cell cycle reentry
Mol Cell Biol
Estrogen regulates activity of cyclin-dependent kinases and retinoblastoma protein phosphorylation in breast cancer cells
Mol Endocrinol
17beta-Estradiol induces cyclin D1 gene transcription, p36D1–p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells
Oncogene
Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4
Mol Cell Biol
TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors
EMBO J
Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors
EMBO J
The nuclear hormone receptor coactivator SRC-1 is a specific target of p300
Proc Natl Acad Sci USA
The CBP co-activator is a histone acetyltransferase
Nature
Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1
Genes Dev
P/CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor
Proc Natl Acad Sci USA
Mechanism of estrogen activation of c-myc oncogene expression
Oncogene
Progesterone, in addition to estrogen, induces cyclin D1 expression in the murine mammary epithelial cell, in vivo
Endocrinology
Cited by (187)
In-vitro and in-vivo assessment of pH-responsive core–shell nanocarrier system for sequential delivery of methotrexate and 5-fluorouracil for the treatment of breast cancer
2023, International Journal of PharmaceuticsMammary gland development in male rats perinatally exposed to propiconazole, glyphosate, or their mixture
2023, Environmental Toxicology and PharmacologyOverview of the miR-29 family members' function in breast cancer
2023, International Journal of Biological MacromoleculesAMG900 as novel inhibitor of the translationally controlled tumor protein
2021, Chemico-Biological InteractionsNRIP1 regulates cell proliferation in lung adenocarcinoma cells
2024, Journal of Biochemistry