Interrelation of Cyclin D1, Cyclin E, and p27Kip1 Expression on Tissue Arrays of Breast Cancer

Long-term growth inhibition, arrest in G1phase and reduced activity of both cyclin D1-Cdk4 and cyclin E-Cdk2 are elicited by progestin treatment of breast cancer cells in culture. Decreased cyclin expression, induction of p18INK4cand increased association of the CDK inhibitors p21WAF1/Cip1and p27Kip1with cyclin E-Cdk2 have been implicated in these responses. To determine the role of decreased cyclin expression, T-47D human breast cancer cells constitutively expressing cyclin D1 or cyclin E were treated with the progestin ORG 2058. Overexpression of cyclin E had only a modest effect on growth inhibition. Although cyclin E expression was maintained during progestin treatment, cyclin E-Cdk2 activity decreased by ∼60%. This was accompanied by p27Kip1association with cyclin E-Cdk2, indicating that both cyclin E down-regulation and p27Kip1recruitment contribute to the decrease in activity. In contrast, overexpression of cyclin D1 induced progestin resistance and cell proliferation continued despite decreased cyclin E-Cdk2 activity. Progestin treatment of cyclin D1-overexpressing cells was associated with increased p27Kip1association with cyclin E-Cdk2. Thus the ability of cyclin D1 to confer progestin resistance does not depend on sequestration of p27Kip1away from cyclin E-Cdk2, providing evidence for a critical function of cyclin D1 other than as a high-capacity “sink” for p27Kip1. These data indicate that regulation of cyclin D1 is a critical element of progestin inhibition in breast cancer cells and suggest that breast cancers overexpressing cyclin D1 may respond poorly to progestin therapy.

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Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution.

Molecular and Cellular Biology ◽

10.1128/mcb.17.7.4059 ◽

1997 ◽

Vol 17 (7) ◽

pp. 4059-4069 ◽

Cited By ~ 169

Author(s):

M D Planas-Silva ◽

R A Weinberg

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cyclin D1 ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cyclin E ◽

Tamoxifen Treatment ◽

Steroid Dependent ◽

Dependent Cell ◽

Mammary Carcinoma Cells

In order to elucidate the mechanisms by which estrogens and antiestrogens modulate the growth of breast cancer cells, we have characterized the changes induced by estradiol that occur during the G1 phase of the cell cycle of MCF-7 human mammary carcinoma cells. Addition of estradiol relieves the cell cycle block created by tamoxifen treatment, leading to marked activation of cyclin E-cdk2 complexes and phosphorylation of the retinoblastoma protein within 6 h. Cyclin D1 levels increase significantly while the levels of cyclin E, cdk2, and the p21 and p27 cdk inhibitors are relatively constant. However, the p21 cdk inhibitor shifts from its association with cyclin E-cdk2 to cyclin D1-cdk4, providing an explanation for the observed activation of the cyclin E-cdk2 complexes. These results support the notion that cyclin D1 has an important role in steroid-dependent cell proliferation and that estrogen, by regulating the activities of G1 cyclin-dependent kinases, can control the proliferation of breast cancer cells.

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Expression of cell cycle-regulatory proteins Rb, p16/MTS1, p27/KIP1, p21/WAF1, cyclin D1 and cyclin E in breast cancer: Correlations with expression of activating protein-1 family members

International Journal of Cancer ◽

10.1002/1097-0215(20000815)87:4<468::aid-ijc2>3.0.co;2-r ◽

2000 ◽

Vol 87 (4) ◽

pp. 468-472 ◽

Cited By ~ 32

Author(s):

Karin Milde-Langosch ◽

Ana-Maria Bamberger ◽

Carola Methner ◽

Gabriele Rieck ◽

Thomas Löning

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cyclin D1 ◽

Cyclin E ◽

Family Members ◽

Regulatory Proteins ◽

Cell Cycle Regulatory Proteins ◽

P21 Waf1 ◽

P27 Kip1

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Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E

Endocrine Related Cancer ◽

10.1677/erc.1.00993 ◽

2005 ◽

Vol 12 (Supplement_1) ◽

pp. S47-S59 ◽

Cited By ~ 133

Author(s):

Alison J Butt ◽

Catriona M McNeil ◽

Elizabeth A Musgrove ◽

Robert L Sutherland

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Cyclin E ◽

Endocrine Resistance ◽

Cycle Progression ◽

Er Positive ◽

Oestrogen Signalling

Antioestrogen therapy is a highly effective treatment for patients with oestrogen-receptor (ER)-positive breast cancer, emphasising the central role of oestrogen action in the development and progression of this disease. However, effective antioestrogen treatment is often compromised by acquired endocrine resistance, prompting the need for a greater understanding of the down-stream mediators of oestrogen action that may contribute to this effect. Recent studies have demonstrated a critical link between oestrogen’s mitogenic effects and cell cycle progression, particularly at the G1 to S transition where key effectors of oestrogen action are c-Myc and cyclin D1, which converge on the activation of cyclin E-cdk2. These components are rapidly upregulated in response to oestrogen, and can mimic its actions on cell cycle progression, including re-initiating cell proliferation in antioestrogen-arrested cells. Here we review the roles of c-Myc, cyclin D1 and cyclin E in oestrogen action and endocrine resistance, and identify their potential as markers of disease progression and endocrine responsiveness, and as novel therapeutic targets in endocrine-resistant breast cancer.

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Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells.

Endocrine Related Cancer ◽

10.1677/erc.0.0100179 ◽

2003 ◽

pp. 179-186 ◽

Cited By ~ 187

Author(s):

S F Doisneau-Sixou ◽

C M Sergio ◽

J S Carroll ◽

R Hui ◽

E A Musgrove ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Cyclin E ◽

Estrogen Regulation ◽

Cycle Progression ◽

P21 Waf1 ◽

Regulation Of Cell Cycle ◽

And Function

The central involvement of estrogen in the development of the mammary gland and in the genesis of breast cancer has lent impetus to studies of the links between estrogen action and the cell cycle machinery. Recent studies of the estrogenic regulation of molecules with known roles in the control of G1/S phase progression have resulted in significant advances in understanding these links. Estrogens independently regulate the expression and function of c-Myc and cyclin D1 and the induction of either c-Myc or cyclin D1 is sufficient to recapitulate the effects of estrogen on cell cycle progression. These pathways converge at the activation of cyclin E-Cdk2 complexes. The active cyclin E-Cdk2 complexes are depleted of the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) because of estrogen-mediated inhibition of nascent p21(WAF1/CIP1). Insulin and estrogen synergistically stimulate cell cycle progression, and the ability of estrogen to antagonize an insulin-induced increase in p21(WAF1/CIP1) gene expression appears to underlie this effect. Antiestrogen treatment of MCF-7 cells leads to an acute decrease of c-Myc expression, a subsequent decline in cyclin D1, and ultimately arrest of cells in a state with features characteristic of quiescence. An antisense-mediated decrease in c-Myc expression results in decreased cyclin D1 expression and inhibition of DNA synthesis, mimicking the effects of antiestrogen treatment and emphasizing the importance of c-Myc as an estrogen/antiestrogen target. These data identify c-Myc, cyclin D1, p21(WAF1/CIP1) and cyclin E-Cdk2 as central components of estrogen regulation of cell cycle progression and hence as potential downstream targets that contribute to the role of estrogen in oncogenesis.

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