Elsevier

The Breast

Volume 15, Issue 6, December 2006, Pages 718-727
The Breast

REVIEW
Cyclin D1 and breast cancer

https://doi.org/10.1016/j.breast.2006.02.005Get rights and content

Summary

Cyclin D1 is one of the frequently overexpressed proteins and one of the commonly amplified genes in breast cancer. This article reviews the roles of cyclin D1 in cell-cycle regulation (normal and abnormal), mammary gland development and carcinogenesis and the relationship to oestrogen in breast tissues. It concludes by presenting the clinical, prognostic and therapeutic implications of our current knowledge of cyclin D1 in 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

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