Cyclin D1 Is Necessary for Tamoxifen-Induced Cell Cycle Progression in Human Breast Cancer Cells

Kilker, Robin L.; Planas-Silva, Maricarmen D.

doi:10.1158/0008-5472.can-06-1755

Cited by 59 publications

(53 citation statements)

References 44 publications

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“…This result indicates that the levels of cyclin D1 did not simply reflect the growth rate but rather that growth in estrogen-depleted/tamoxifen-containing medium requires elevated levels of cyclin D1. This result further supports the observation reported by others that inhibition of cyclin D1 by siRNA abolishes the ability of tamoxifen-resistant clones to grow in the presence of tamoxifen (27). In agreement with our finding that STAT3 and phospho-STAT3 levels were elevated in cyclin D1-overexpressing cells in the presence of tamoxifen, this was also observed in tamoxifen-resistant clones (Fig.…”

Section: Cyclin D1 Is Elevated In Tamoxifen-resistant T47d Clonessupporting

confidence: 94%

Tamoxifen Stimulates the Growth of Cyclin D1–Overexpressing Breast Cancer Cells by Promoting the Activation of Signal Transducer and Activator of Transcription 3

2008

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De novo or acquired resistance to tamoxifen is a major clinical challenge for the management of estrogen receptor (ER)-positive breast cancers. Although cyclin D1 overexpression is associated with a better outcome for breast cancer patients, its overexpression is also linked to tamoxifen resistance. We previously reported that the beneficial effect of cyclin D1 correlates with its ability to repress the antiapoptotic transcription factor signal transducer and activator of transcription 3 (STAT3). In contrast, molecular pathways linking overexpression of cyclin D1 to tamoxifen resistance have not been established. In the current study, the effect of tamoxifen on the growth of genetically matched high or low cyclin D1-expressing breast cancer cells was characterized and the interactions between cyclin D1, ER, and STAT3 in response to tamoxifen treatment were determined. We show that repression of STAT3 by cyclin D1 inhibits cell growth on Matrigel and in tumors in vivo; however, treatment with tamoxifen abolishes cyclin D1-mediated repression of STAT3 and growth suppression. We show that tamoxifen induces a redistribution of cyclin D1 from STAT3 to the ER, which results in the activation of both STAT3 and the ER. These results offer a molecular mechanism for the dual effect of cyclin D1 overexpression in breast cancer and support the notion that the level of cyclin D1 expression and activated STAT3 are important markers to predict response to tamoxifen treatment. [Cancer Res 2008;68(3):852-60]

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Section: Cyclin D1 Is Elevated In Tamoxifen-resistant T47d Clonessupporting

confidence: 94%

Tamoxifen Stimulates the Growth of Cyclin D1–Overexpressing Breast Cancer Cells by Promoting the Activation of Signal Transducer and Activator of Transcription 3

2008

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“…Cyclin D1 is thought to contribute to the growth of MCF-7 and other breast cancer cells (42)(43)(44) and to tamoxifen-stimulated growth of breast cancer cells (45). As previously reported (43,46), E 2 -ER␣ stimulated a 2-3-fold increase in cyclin D1 mRNA that was blocked by 10 M TPSF (Fig.…”

Section: Tpsf Is a Structure-specific Inhibitor That Acts Outside Of supporting

confidence: 74%

“…The lower levels of ER␣ in ZR-75 compared with MCF-7 cells (54) may be responsible for the greater potency of TPSF in ZR-75 cells. Some tamoxifen-resistant breast cancers regress after tamoxifen withdrawal, suggesting that tamoxifen stimulates tumor growth (45,(55)(56)(57). The MCF7ER␣HA cell line is a model for tamoxifen-stimulated breast cancer, where tamoxifen and OHT act as full agonists (Fig.…”

Section: Tpsf Inhibits E 2 -Er␣-dependent Growth Of Tamoxifenresistanmentioning

confidence: 99%

A Noncompetitive Small Molecule Inhibitor of Estrogen-regulated Gene Expression and Breast Cancer Cell Growth That Enhances Proteasome-dependent Degradation of Estrogen Receptor α

Kretzer

Cherian

Mao

et al. 2010

Journal of Biological Chemistry

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The mechanisms responsible for 17␤-estradiol (E 2 )-stimulated breast cancer growth and development of resistance to tamoxifen and other estrogen receptor ␣ (ER␣) antagonists are not fully understood. We describe a new tool for dissecting ER␣ action in breast cancer, p-fluoro-4-(1,2,3,6,-tetrahydro-1,3-dimethyl-2-oxo-6-thionpurin-8-ylthio) (TPSF), a potent small-molecule inhibitor of estrogen receptor ␣ that does not compete with estrogen for binding to ER␣. TPSF noncompetitively inhibits estrogen-dependent ER␣-mediated gene expression with little inhibition of transcriptional activity by NF-B or the androgen or glucocorticoid receptor. TPSF inhibits E 2 -ER␣-mediated induction of the proteinase inhibitor 9 gene, which is activated by ER␣ binding to estrogen response element DNA, and the cyclin D1 gene, which is induced by tethering ER␣ to other DNA-bound proteins. TPSF inhibits anchorage-dependent and anchorage-independent E 2 -ER␣-stimulated growth of MCF-7 cells but does not inhibit growth of ER-negative MDA-MB-231 breast cancer cells. TPSF also inhibits ER␣-dependent growth in three cellular models for tamoxifen resistance; that is, 4-hydroxytamoxifen-stimulated MCF7ER␣HA cells that overexpress ER␣, fully tamoxifen-resistant BT474 cells that have amplified HER-2 and AIB1, and partially tamoxifen-resistant ZR-75 cells. TPSF reduces ER␣ protein levels in MCF-7 cells and several other cell lines without altering ER␣ mRNA levels. The proteasome inhibitor MG132 abolished down-regulation of ER␣ by TPSF. Thus, TPSF affects receptor levels at least in part due to its ability to enhance proteasome-dependent degradation of ER␣. TPSF represents a novel class of ER inhibitor with significant clinical potential. Estrogen receptor ␣ (ER␣)3 is a well studied member of the steroid/nuclear receptor family of transcription regulators. ER␣ acts in the nucleus to regulate gene expression by binding to estrogen response elements (EREs) and related DNA sequences (1-4) and through association with transcription factors bound at SP1 and AP-1 DNA binding sites (4 -7). In response to high affinity estrogen binding, ER␣ dimerizes, binds to ERE DNAs, and undergoes a conformational change in the ligand binding domain that facilitates the recruitment of coactivators (8). Bound coactivators promote assembly of a multiprotein complex that enables chromatin remodeling and stabilization of an active transcription complex (9 -11). In contrast, antagonist-occupied ER␣ recruits corepressors (12).At detection, growth of most human breast cancers depends on 17␤-estradiol (E 2 ) binding to ER␣ (13-16). Treatment strategies that inhibit estrogen-dependent breast cancer include selective ER modulators such as tamoxifen, which binds in the ER␣ ligand binding pocket, and aromatase inhibitors, which block estrogen production. Nearly half of patients treated with aromatase inhibitors develop resistance (17). The long-term effectiveness of tamoxifen is limited by the development of resistance in nearly all patients with metastatic breast cancer and in ϳ4...

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“…4A; ref. 29). The markedly reduced levels of total IGF-IR suggest that IGF-IR is dependent on ER for expression and is therefore reduced upon ER inhibition.…”

Section: Resultsmentioning

confidence: 99%

Tamoxifen Resistance in Breast Tumors Is Driven by Growth Factor Receptor Signaling with Repression of Classic Estrogen Receptor Genomic Function

et al. 2008

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Not all breast cancers respond to tamoxifen, and many develop resistance despite initial benefit. We used an in vivo model of estrogen receptor (ER)-positive breast cancer (MCF-7 xenografts) to investigate mechanisms of this resistance and develop strategies to circumvent it. Epidermal growth factor receptor (EGFR) and HER2, which were barely detected in control estrogen-treated tumors, increased slightly with tamoxifen and were markedly increased when tumors became resistant. Gefitinib, which inhibits EGFR/HER2, improved the antitumor effect of tamoxifen and delayed acquired resistance, but had no effect on estrogen-stimulated growth. Phosphorylated levels of p42/44 and p38 mitogen-activated protein kinases (both downstream of EGFR/HER2) were increased in the tamoxifen-resistant tumors and were suppressed by gefitinib.

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Cyclin D1 Is Necessary for Tamoxifen-Induced Cell Cycle Progression in Human Breast Cancer Cells

Cited by 59 publications

References 44 publications

Tamoxifen Stimulates the Growth of Cyclin D1–Overexpressing Breast Cancer Cells by Promoting the Activation of Signal Transducer and Activator of Transcription 3

Tamoxifen Stimulates the Growth of Cyclin D1–Overexpressing Breast Cancer Cells by Promoting the Activation of Signal Transducer and Activator of Transcription 3

A Noncompetitive Small Molecule Inhibitor of Estrogen-regulated Gene Expression and Breast Cancer Cell Growth That Enhances Proteasome-dependent Degradation of Estrogen Receptor α

Tamoxifen Resistance in Breast Tumors Is Driven by Growth Factor Receptor Signaling with Repression of Classic Estrogen Receptor Genomic Function

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