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

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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Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells.

10.1158/0008-5472.sabcs-2130 ◽

2009 ◽

Cited By ~ 2

Author(s):

A D'Alessio ◽

A De Luca ◽

MR Maiello ◽

C Palumbo ◽

A Rachiglio ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Signal Transduction ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Regulatory Proteins ◽

Cell Cycle Regulatory Proteins ◽

Regulation Of Cell Cycle

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Abstract 305: TET blocks cell cycle progression in pancreatic cancer cells at G1-S boundary by decreasing cyclin D1 and increasing CDK inhibitors (CKIs), p21 (WAF1, Cip1) and p27 (Kip1)

10.1158/1538-7445.am2017-305 ◽

2017 ◽

Cited By ~ 1

Author(s):

Karnika Singh ◽

Qin Dong ◽

Sweaty Koul ◽

Hari K. Koul

Keyword(s):

Cell Cycle ◽

Pancreatic Cancer ◽

Cyclin D1 ◽

Cancer Cells ◽

Cell Cycle Progression ◽

Cdk Inhibitors ◽

Cycle Progression ◽

Pancreatic Cancer Cells ◽

P21 Waf1 ◽

P27 Kip1

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Results of immunohistochemical staining for cell cycle regulators predict the recurrence of atypical meningiomas

Journal of Neurosurgery ◽

10.3171/2014.7.jns132661 ◽

2014 ◽

Vol 121 (5) ◽

pp. 1189-1200 ◽

Cited By ~ 13

Author(s):

Min Soo Kim ◽

Kyu Hong Kim ◽

Eun Hee Lee ◽

Young Min Lee ◽

Sung-Hun Lee ◽

...

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Immunohistochemical Staining ◽

Regulatory Proteins ◽

Incomplete Resection ◽

Presenting Symptoms ◽

Cell Cycle Regulatory Proteins ◽

Atypical Meningiomas ◽

Mib 1

Object The aim of this study was to evaluate the role of certain cell-cycle regulatory proteins in the recurrence of atypical meningiomas. These proteins were analyzed with immunohistochemical staining to identify predisposing factors for the recurrence of atypical meningiomas. Methods The authors retrospectively reviewed the medical records of patients with atypical meningiomas diagnosed in the period from January 2000 to June 2012 at the Department of Neurosurgery at Samsung Changwon Hospital and Dong-A University Medical Center. Clinical data included patient sex and age at the time of surgery, presenting symptoms at diagnosis, location and size of tumor, extent of surgery, use of postoperative radiotherapy, duration of follow-up, and recurrence. Immunohistochemical staining for cell-cycle regulatory proteins (p16, p15, p21, p27, cyclin-dependent kinase [CDK] 4 and 6, phosphorylated retinoblastoma [pRB] protein, and cyclin D1) and proliferative markers (MIB-1 antigen, mitosis, and p53) was performed on archived paraffin-embedded tissues obtained during resection. The recurrence rate and time to recurrence were assessed using Kaplan-Meier analysis. Results Of the 67 atypical meningiomas eligible for analysis, 26 (38.8%) recurred during the follow-up period (mean duration 47.7 months, range 8.4–132.1 months). Immunohistochemically, there was overstaining for p16 in 44 samples (65.7%), for p15 in 21 samples (31.3%), for p21 in 25 samples (37.3%), for p27 in 32 samples (47.8%), for CDK4 in 38 samples (56.7%), for CDK6 in 26 samples (38.8%), for pRB protein in 42 samples (62.7%), and for cyclin D1 in 49 samples (73.1%). Multivariate analysis using the Cox proportional-hazards regression model showed that incomplete resection (HR 4.513, p < 0.001); immunohistochemical understaining for p16 (HR 3.214, p < 0.001); immunohistochemical overstaining for CDK6 (HR 3.427, p < 0.001), pRB protein (HR 2.854, p = 0.008), and p53 (HR 2.296, p = 0.040); and increased MIB-1 labeling index (HR 2.665, p = 0.013) and mitotic index (HR 2.438, p = 0.024) predicted the recurrence of atypical meningiomas after resection. Conclusions Findings in this study indicated that p16, CDK6, and pRB protein were associated with the recurrence of atypical meningiomas.

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