The RB tumor suppressor: a gatekeeper to hormone independence in prostate cancer?
Kay F. Macleod
Kay F. Macleod
Published November 22, 2010
Citation Information: J Clin Invest. 2010;120(12):4179-4182. https://doi.org/10.1172/JCI45406.
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Commentary

The RB tumor suppressor: a gatekeeper to hormone independence in prostate cancer?

Abstract

The retinoblastoma tumor suppressor gene (RB1; encoding RB) is often cited as a gatekeeper, whose inactivation — direct or indirect — is a rate-limiting step for tumor initiation. However, in this issue of the JCI, Sharma et al. show that RB1 loss is a late event in human prostate cancer that is coincident with the emergence of castrate-resistant metastatic disease. This role for RB1 was linked to both E2F transcription factor 1–driven upregulation of the androgen receptor (AR) and increased recruitment of the AR to target gene promoters. This unexpected function for RB1 in late-stage cancer calls upon us to reassess the significance of RB1 inactivation in other cancers in terms of its timing, function in disease etiology, and relevance for cancer therapy.

Authors

Kay F. Macleod

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Figure 2

Understanding the role of RB in preventing progression to CRPC at the cellular level.

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Understanding the role of RB in preventing progression to CRPC at the ce...
The progression of prostate cancer through different stages, from PIN to adenocarcinoma to metastatic CRPC, has been associated with activation of specific oncogenes, such as Myc, and loss of key tumor suppressors, such as PTEN, at early stages of tumorigenesis (6). Detectable loss of RB1 at late stages upon progression to CRPC raises the intriguing question as to whether androgen deprivation is selecting for androgen independence through genetic loss/epigenetic silencing of RB1 in previously androgen-dependent cells, or whether such RB-deficient androgen-independent cells were present in low abundance throughout tumorigenesis, but now have a growth advantage over RB-proficient androgen-dependent cells, allowing them to expand to become the dominant tumor cell type represented.