RB Loss Abrogates Cell Cycle Control and Genome Integrity to Promote Liver Tumorigenesis

Mayhew, Christopher N.; Carter, Scott L.; Fox, Sejal R.; Sexton, Charlene R.; Reed, Christopher A.; Srinivasan, Sundar; Liu, Xiangdong; Wikenheiser-Brokamp, Kathryn A.; Boivin, Gregory P.; Lee, Ju Seog; Aronow, Bruce J.; Thorgeirsson, Snorri S.; Knudsen, Erik S.

doi:10.1053/j.gastro.2007.06.025

Cited by 79 publications

(73 citation statements)

References 34 publications

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“…We previously developed a gene expression signature of RB loss, using genetically defined models of RB deletion. The gene signature has been validated across multiple platforms and is a reliable measure of RB transcriptional corepressor function (9)(10)(11)(12). Analyses showed that loss of RB function was significantly overrepresented in CRPC but not primary disease ( Figure 1B), consistent with Figure 1A.…”

Section: Rb Loss Is Overrepresented In Pca Metastases and Castration-supporting

confidence: 70%

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

et al. 2010

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Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control. In analyses of human prostate cancer samples, RB loss was infrequently observed in primary disease and was predominantly associated with transition to the incurable, castration-resistant state. Further analyses revealed that loss of the RB1 locus may be a major mechanism of RB disruption and that loss of RB function was associated with poor clinical outcome. Modeling of RB dysfunction in vitro and in vivo revealed that RB controlled nuclear receptor networks critical for tumor progression and that it did so via E2F transcription factor 1-mediated regulation of androgen receptor (AR) expression and output. Through this pathway, RB depletion induced unchecked AR activity that underpinned therapeutic bypass and tumor progression. In agreement with these findings, disruption of the RB/E2F/nuclear receptor axis was frequently observed in the transition to therapy resistance in human disease. Together, these data reveal what we believe to be a new paradigm for RB function in controlling prostate tumor progression and lethal tumor phenotypes. IntroductionRetinoblastoma (RB; encoded by RB1), a tumor suppressor protein, is a critical negative regulator of tumor development. RB prevents tumorigenesis by suppressing cell cycle progression (1). However, the role of RB in tumor progression is poorly understood, and the clinical importance of RB loss during this process has not been well considered. Here, we identified a clinically relevant function for RB in tumor progression, manifest through control of hormone signaling networks.The function of RB in cell cycle control has been well described (1). Conditions favoring cell cycle arrest induce RB hypophosphorylation and activation. Active RB binds to promoters of genes required for S-phase entry (e.g., CCNA2 and MCM7) and, through association with the SWI/SNF complex and corepressor molecules (e.g., Sin3B), elicits transcriptional corepression. Many RB target genes are positively regulated by activator E2F transcription factors, supporting the current model that RB acts by suppressing E2F-mediated transcriptional activation. Indeed, the minimal transcriptional repression and tumor suppression domain of RB contains the E2F binding motif. E2F-independent functions of RB have been identified (2), but the contribution of these functions to tumor suppression is uncertain. Thus, contemporary views of RB suggest that the protein prevents cell cycle deregulation and tumor development through suppression of activator E2Fs.

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Section: Rb Loss Is Overrepresented In Pca Metastases and Castration-supporting

confidence: 70%

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

et al. 2010

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“…In good agreement with the epidemiologic observations, mice with a liver-specific ablation of the Rb gene showed aberrant ploidy and increased multiplicity of liver tumors when exposed to DEN (Mayhew et al 2005;Mayhew et al 2007;Srinivasan et al 2007). To explore the role of AHR/RB/TGF-β interactions in liver tumorigenesis, we have examined the expression status of Tgfb genes, tumor suppressor genes, Ahr and several of its downstream targets in DEN-induced liver tumors and normal livers of mice with a liver-specific ablation of the Rb gene and in their wild-type littermates.…”

Section: Introductionsupporting

confidence: 85%

“…Genotypes were determined by standard PCR of tail DNA and deletion or retention of the Rb gene was confirmed by genotyping the mouse livers themselves. Characterization of these tumors has been reported elsewhere (Mayhew et al 2005;Mayhew et al 2007;Srinivasan et al 2007). …”

Section: Micementioning

confidence: 98%

Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Mayhew

Schnekenburger

et al. 2008

Toxicology

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biologic and toxic effects of its xenobiotic ligands. In recent years it has become evident that in the absence of ligand the AHR promotes cell cycle progression and that its activation by high-affinity ligands results in interactions with the retinoblastoma protein (RB) that lead to perturbation of the cell cycle, G 0 /G 1 arrest, diminished capacity for DNA replication and inhibition of cell proliferation. Hence, the AHR has diametrically opposed pro-proliferative and anti-proliferative functions that have yet to be reconciled at the molecular level. Work from our own and from other laboratories suggests that the AHR may function as a tumor suppressor gene that becomes silenced in the process of tumor formation. To develop preliminary support for a more thorough examination of this hypothesis we characterized the expression levels of various tumor suppressor genes, transforming growth factor-β (Tgfb) genes and the Ahr gene in liver tumor samples from mice with a liver-specific RB ablation and their wild-type littermates. In tumors arising in RB-positive livers, Cdkn2d and Tgfb1 were repressed and Cdkn2c, Tgfb2, Tgfb3 and Pai1 were induced, whereas in RB-negative tumors, only Cdkn2c and Tgfb3 were induced. Ahr was significantly repressed in tumors from both sets of mice, supporting the concept that Ahr silencing may be associated with cancer progression.

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“…25) ) male and female mice were treated with the liver-specific carcinogen diethylnitrosamine (DEN; ref. 26) and examined at 9 months of age. Deletion of E2F7/8 in livers was confirmed by PCR genotyping (Supplemental Figure 1C).…”

Section: Introductionmentioning

confidence: 99%

E2f8 mediates tumor suppression in postnatal liver development

Kent¹,

Rakijas²,

Pandit³

et al. 2016

Journal of Clinical Investigation

100

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RB Loss Abrogates Cell Cycle Control and Genome Integrity to Promote Liver Tumorigenesis

Cited by 79 publications

References 34 publications

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

E2f8 mediates tumor suppression in postnatal liver development

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