Cyclin E dependent kinase activity in human breast cancer in relation to cyclin E, p27 and p21 expression and retinoblastoma protein phosphorylation

Lodén, Martin; Nielsen, Niels Hilmer; Roos, Göran; Emdin, Stefan O.; Landberg, Göran

doi:10.1038/sj.onc.1202488

Cited by 44 publications

(34 citation statements)

References 42 publications

(48 reference statements)

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“…A number of studies have demonstrated a strong correlation between elevated levels of cyclin E1 and tumor progression and mortality (Muller-Tidow et al, 2001;Geng et al, 2001;Keyomarsi et al, 1994; GrayBablin et al, 1996;Loden et al, 1999;Nielson et al, 1996;Porter et al, 1997;Bortner and Rosenberg, 1997). In addition, there is a correlation between elevated cyclin E1-Cdk2 kinase activity, increased phosphorylation of Rb, and increased rates of tumor cell proliferation in breast cancers (Loden et al, 1999).…”

Section: Resultsmentioning

confidence: 99%

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Deregulation of Cyclin E2 expression and associated kinase activity in primary breast tumors

et al. 2002

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The increased expression of G 1 cyclins has been associated with the many types of human tumors. In primary solid tumors however, the expression and activity of cyclin E2, the newest member of the G 1 cyclin family, is largely unknown. In this study we have analysed the expression of the E-type cyclins in primary solid tumors from breast, lung, uterus, ovary, colon, and rectal tissues. Relative gene expression was analysed by quantitative real-time reverse transcription polymerase chain reaction (Taqman). The levels of cyclin E1 and cyclin E2 were significantly elevated (23 vs 38%, respectively) in primary breast tumor samples relative to normal breast tissue controls. We also observed an inverse correlation between the expression of cyclin E1/ E2 and estrogen receptor in breast tumors. Our results demonstrate that the expression and associated catalytic activity for both cyclin E1 and cyclin E2 is elevated in primary breast tumors when compared to normal breast tissue. The increased level of cyclin E2 in breast tumors suggests that, similar to cyclin E1, it may contribute to the pathogenesis of breast cancer. Oncogene (2002) 21, 8529 -8534. doi:10.1038/sj.onc. 1206035Keywords: Cyclin E2; Cyclin E1; Cdk2; breast tumor Results and DiscussionA number of studies have demonstrated a strong correlation between elevated levels of cyclin E1 and tumor progression and mortality (Muller-Tidow et al., 2001;Geng et al., 2001;Keyomarsi et al., 1994; GrayBablin et al., 1996;Loden et al., 1999;Nielson et al., 1996;Porter et al., 1997;Bortner and Rosenberg, 1997). In addition, there is a correlation between elevated cyclin E1-Cdk2 kinase activity, increased phosphorylation of Rb, and increased rates of tumor cell proliferation in breast cancers (Loden et al., 1999). However, the expression and activity of cyclin E2 in solid tumors is largely unknown. Our initial characterization of cyclin E2 expression in tumor derived cell lines and primary mouse embryonic fibroblasts lacking Rb demonstrated a strong association between elevated levels of cyclin E2 and the functional inactivation of Rb (Gudas et al., 1999;Geng et al., 2001). We also demonstrated that cyclin E2 expression was elevated in lung tumor-derived cell lines in comparison to cell lines derived from normal lung tissue. Two recent studies evaluated the expression of cyclin E2 in early stage primary Non-Small Cell Lung Carcinoma (NSCLC) and in primary breast carcinoma (Muller-Tidow et al., 2001;Geng et al., 2001). Interestingly, no significant elevation of cyclin E2 transcript levels was found in any of the lung tumors. In contrast, increased expression of cyclin E2 was observed in 25% of primary breast carcinomas.To confirm and extend these recent observations we have analysed the expression of cyclin E2 in a variety of primary tumors and determined the catalytic activity associated with both cyclin E2 and cyclin E1 in primary breast tumors. Quantitative real-time RT -PCR (Taqman) analysis of primary tumor RNAs was used to determine the Relative Gene Expression (RGE) val...

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Section: Resultsmentioning

confidence: 99%

“…In addition, there is a correlation between elevated cyclin E1-Cdk2 kinase activity, increased phosphorylation of Rb, and increased rates of tumor cell proliferation in breast cancers (Loden et al, 1999). However, the expression and activity of cyclin E2 in solid tumors is largely unknown.…”

Section: Resultsmentioning

confidence: 99%

Deregulation of Cyclin E2 expression and associated kinase activity in primary breast tumors

et al. 2002

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“…In breast cancer cells, Cdk2 activity does not necessarily correlate with cyclin E levels (35) and may instead reflect the relative amounts of cyclin E and p27Kip1 (36). Cdk2 activity is turned on in quiescent MCF-7 cells by E2 without significant changes in cyclin E expression and instead relates to changes in association of cyclin E-Cdk2 with CIP͞KIP Cdk inhibitors (37).…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor β inhibits 17β-estradiol-stimulated proliferation of the breast cancer cell line T47D

Ström

Hartman

Foster

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

499

392

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Estrogen receptor (ER) β counteracts the activity of ERα in many systems. In agreement with this, we show in this study that induced expression of ERβ in the breast cancer cell line T47D reduces 17β-estradiol-stimulated proliferation when expression of ERβ mRNA equals that of ERα. Induction of ERβ reduces growth of exponentially proliferating cells with a concomitant decrease in components of the cell cycle associated with proliferation, namely cyclin E, Cdc25A (a key regulator of Cdk2), p45 Skp2 (a key regulator of p27 Kip1 proteolysis), and an increase in the Cdk inhibitor p27 Kip1 . We also observed a reduced Cdk2 activity. These findings suggest a possible role for ERβ in breast cancer and imply that ERβ-specific ligands may reduce proliferation of ER-positive breast cancer cells through actions on the G 1 phase cell-cycle machinery.

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“…High levels of cyclin E-CDK2 activity in these tumors correlate with a high cyclin E/low p27 Kip1 phenotype (13) …”

Section: ) Functional Expression Of P27mentioning

confidence: 92%

Estrogens Down-regulate p27 in Breast Cancer Cells through Skp2 and through Nuclear Export Mediated by the ERK Pathway

Foster

Fernando

Ishida

et al. 2003

Journal of Biological Chemistry

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The cyclin-dependent kinase (CDK) inhibitor p27Kip1 plays a key role in growth and development of the mammary epithelium and in breast cancer. p27Kip1 levels are regulated through ubiquitin/proteasome-mediated proteolysis, promoted by CDK2 and the F box protein Skp2 at the G 1 /S transition, and independent of Skp2 in mid-G 1 . We investigated the respective roles of Skp2 and subcellular localization of p27Kip1 in down-regulation of p27Kip1 induced in MCF-7 cells by estrogens. 17␤-Estradiol treatment increased Skp2 expression in MCF-7 cells; however, this increase was prevented by G 1 blockade mediated by p16Ink4a or the CDK inhibitor roscovitine, whereas down-regulation of p27Kip1 was maintained. Exogenous Skp2 prevented growth arrest of MCF-7 cells by antiestrogen, coinciding with decreased p27Kip1 expression. Under conditions of G 1 blockade, p27Kip1 was stabilized by inhibition of CRM1-dependent nuclear export with leptomycin B or by mutation of p27 Kip1 (Ser 10 3 Ala; S10A) interfering with CRM1/ p27 Kip1 interaction. Antisense Skp2 oligonucleotides and a dominant-interfering Cul-1(1-452) mutant prevented down-regulation of p27 Kip1 S10A, whereas Skp2 overexpression elicited its destruction in mitogen-de- Kip1 in response to estrogen. Our studies indicate that estrogens elicit downregulation of p27Kip1 in MCF-7 cells through Skp2-dependent and -independent mechanisms that depend upon subcellular localization of p27Kip1 and require the participation of mediators of the Ras/Raf-1/ERK signaling pathway.

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Cyclin E dependent kinase activity in human breast cancer in relation to cyclin E, p27 and p21 expression and retinoblastoma protein phosphorylation

Cited by 44 publications

References 42 publications

Deregulation of Cyclin E2 expression and associated kinase activity in primary breast tumors

Deregulation of Cyclin E2 expression and associated kinase activity in primary breast tumors

Estrogen receptor β inhibits 17β-estradiol-stimulated proliferation of the breast cancer cell line T47D

Estrogens Down-regulate p27 in Breast Cancer Cells through Skp2 and through Nuclear Export Mediated by the ERK Pathway

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