Targeting the RB-E2F pathway in breast cancer

Johnson, Jackie; Thijssen, Bram; McDermott, Ultan; Garnett, Mathew J.; Wessels, Lodewyk F.A.; Bernards, René

doi:10.1038/onc.2016.32

Cited by 174 publications

(146 citation statements)

References 66 publications

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“…E2F transcription factors are not frequently mutated, but may be involved large-scale chromosomal aberrations such as loss of 16q [Johnson et al 2016]. p21 Cip1 expression is frequently reduced as a consequence of TP53 mutation [Musgrove et al 1995] or Myc overexpression [Mukherjee and Conrad, 2005], and p27 Kip1 expression is reduced as a result of HER2 amplification [Chu et al 2008].…”

Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

“…Accumulating evidence also shows roles for the E2F transcription factors beyond that in the cell cycle [Johnson et al 2016], including roles in promoting invasiveness [Yoon et al 2006] and metastatization [Andrechek, 2015].…”

Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

“…According to TCGA data, loss of Rb due to RB1 gene deletion occurs overall in 2-4% of breast cancers, and loss due to RB1 truncating mutations in 1-3% [Johnson et al 2016], depending on breast cancer subtype, with up to 20% mutation/loss rate in basal-like tumors [Cancer Genome Atlas Network, 2012]. This leads to constitutive activation of E2F and induction of cyclin E and CDK2, independently from cyclin D-CDK4/6 activation, and is frequently accompanied by upregulation of p16 [Subhawong et al 2009] due to a feedback loop [Kotake et al 2007].…”

Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

“…CDKN2A is deleted in 3-8% of breast cancers, more frequently in the triple-negative subtype [Johnson et al 2016;Cairns et al 1995], and may be mutated or silenced by promoter methylation [Ruas and Peters, 1998]. …”

Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

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Progress with palbociclib in breast cancer: latest evidence and clinical considerations

et al. 2016

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Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HRpositive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

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Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

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Progress with palbociclib in breast cancer: latest evidence and clinical considerations

et al. 2016

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“…Studies indicated that response of breast cancer cells to PD-0332991 is associated with expression pattern of CDK4/6-pRb-E2F pathway mediated genes such as Rb1, CDKN2A, and cyclin D1 (25)(26)(27). In cell cycle, mitogenic signals induce cyclin D1 gene (CCND1) expression to initiate G1-S transition.…”

Section: Discussionmentioning

confidence: 99%

Meme kanseri kanser kök hücrelerinde PD-0332991 uygulanmasının hücre döngüsü düzenleyici genler üzerine etkisi

Çağlar¹,

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et al. 2018

Ege Tıp Dergisi

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Aim: Palbociclib (PD-0332991) is an inhibitor for cyclin-dependent kinase 4/6 complex and exhibits more activity in luminal ER+ breast cancer. However, sensitivity of breast cancer stem cells (BCSCs) to PD-0332991 treatment and expression patterns of cell cycle regulatory genes after PD-0332991 treatment in BCSCs are still unclear. This study aims to determine response of BCSCs to PD-0332991 treatment. Materials and Methods:An experimental in vitro study was designed on breast cancer cell lines. MCF-7 and BCSCs cell lines were used in this study. Water soluble tetrazolium salt-1 (WST-1) test was used for the cytotoxicity assay. Cell cycle distribution pattern and apoptosis were examined with flow cytometry according to IC50 values at 48th h. Real-Time PCR was used to detect expression profiles of CDKN1A, CHEK1, CDKN2A, CDC25A, and CCND1 genes. Results: PD-0332991 decreased cell proliferation in both cell lines. G0/G1 arrest was detected for both cell lines. There was no apoptotic effect of PD-0332991 on MCF-7 cells and BCSCs. In MCF-7 cells, expression levels of CDKN1A, CDKN2A, and CCND1 genes were increased as 3.11, 3.21, and 1.05 folds, respectively. Expression levels of CHEK1 and CDC25A genes were decreased as 4.75 and 3.73 folds, respectively. In BCSCs, expression levels of CDKN1A, CHEK1, CDKN2A, and CCND1 were decreased as 1.15, 2.01, 1.32, and 1.68 folds, respectively. No expression of CDC25A gene was found in BCSCs group. Conclusion:In this study, it was observed that PD-0332991 leads to different expression profiles for cell cycle regulatory genes between BCSCs and breast cancer cells.Keywords: PD-0332991, breast neoplasms, neoplastic stem cells, G1 cell cycle arrest, cell cycle.

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Short‐term exposure to ethanol induces transcriptional changes in nontumorigenic breast cells

et al. 2023

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Breast cancer is a leading cause of cancer‐related deaths in women. Many genetic and behavioral risk factors can contribute to the initiation and progression of breast cancer, one being alcohol consumption. Numerous epidemiological studies have established a positive correlation between alcohol consumption and breast cancer; however, the molecular basis for this link remains ill defined. Elucidating ethanol‐induced changes to global transcriptional programming in breast cells is important to ultimately understand how alcohol and breast cancer are connected mechanistically. We investigated induced transcriptional changes in response to a short cellular exposure to moderate levels of alcohol. We treated the non‐tumorigenic breast cell line MCF10A, and the tumorigenic breast cell lines MDA‐MB‐231 and MCF7, with ethanol for 6 h, then captured the changes to ongoing transcription using 4‐thiouridine metabolic labeling followed by deep sequencing. Only the MCF10A cell line exhibited statistically significant changes in newly transcribed RNA in response to ethanol treatment. Further experiments revealed that some ethanol‐upregulated genes are sensitive to the dose of alcohol treatment, while others are not. Gene ontology and biochemical pathway analyses revealed that ethanol‐upregulated genes in MCF10A cells are enriched in biological functions that could contribute to cancer development.

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Targeting the RB-E2F pathway in breast cancer

Cited by 174 publications

References 66 publications

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

Meme kanseri kanser kök hücrelerinde PD-0332991 uygulanmasının hücre döngüsü düzenleyici genler üzerine etkisi

Short‐term exposure to ethanol induces transcriptional changes in nontumorigenic breast cells

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