Send to

Choose Destination
J Clin Invest. 2018 Jan 2;128(1):341-358. doi: 10.1172/JCI93566. Epub 2017 Dec 4.

Differential impact of RB status on E2F1 reprogramming in human cancer.

Author information

Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Centre for Integrative Biology, University of Trento, Trento, Italy.
Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Centre for Oncological Research, University of Antwerp, Antwerp, Belgium.
Department of Oncology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.
BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Department of Radiation Oncology, Urology, and Medicine and Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.
Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, New York, USA.
Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, New York, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.


The tumor suppressor protein retinoblastoma (RB) is mechanistically linked to suppression of transcription factor E2F1-mediated cell cycle regulation. For multiple tumor types, loss of RB function is associated with poor clinical outcome. RB action is abrogated either by direct depletion or through inactivation of RB function; however, the basis for this selectivity is unknown. Here, analysis of tumor samples and cell-free DNA from patients with advanced prostate cancer showed that direct RB loss was the preferred pathway of disruption in human disease. While RB loss was associated with lethal disease, RB-deficient tumors had no proliferative advantage and exhibited downstream effects distinct from cell cycle control. Mechanistically, RB loss led to E2F1 cistrome expansion and different binding specificity, alterations distinct from those observed after functional RB inactivation. Additionally, identification of protumorigenic transcriptional networks specific to RB loss that were validated in clinical samples demonstrated the ability of RB loss to differentially reprogram E2F1 in human cancers. Together, these findings not only identify tumor-suppressive functions of RB that are distinct from cell cycle control, but also demonstrate that the molecular consequence of RB loss is distinct from RB inactivation. Thus, these studies provide insight into how RB loss promotes disease progression, and identify new nodes for therapeutic intervention.


Cell Biology; Cell cycle; Oncology; Prostate cancer; Transcription

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center