title: Targeting the RB-E2F pathway in breast cancer.
abstract: Mutations of the retinoblastoma tumor-suppressor gene (RB1) or components regulating the CDK-RB-E2F pathway have been identified in nearly every human malignancy. Re-establishing cell cycle control through cyclin-dependent kinase (CDK) inhibition has therefore emerged as an attractive option in the development of targeted cancer therapy. The most successful example of this today is the use of the CDK4/6 inhibitor palbociclib combined with aromatase inhibitors for the treatment of estrogen receptor-positive breast cancers. Multiple studies have demonstrated that the CDK-RB-E2F pathway is critical for the control of cell proliferation. More recently, studies have highlighted additional roles of this pathway, especially E2F transcription factors themselves, in tumor progression, angiogenesis and metastasis. Specific E2Fs also have prognostic value in breast cancer, independent of clinical parameters. We discuss here recent advances in understanding of the RB-E2F pathway in breast cancer. We also discuss the application of genome-wide genetic screening efforts to gain insight into synthetic lethal interactions of CDK4/6 inhibitors in breast cancer for the development of more effective combination therapies.
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Thijssen
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: U
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Garnett
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: L F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: R
authors.identifier: 0000-0001-8677-3423
authors.initials: R
authors.lastname: Bernards
mesh_terms: D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics*; D050684:E2F Transcription Factors / Q000235:genetics*; D005260:Female; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D056286:Retinoblastoma Binding Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D047072:Aromatase Inhibitors; D050684:E2F Transcription Factors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib