Title:The Role of Tumor Suppressor Dysregulation in Prostate Cancer Progression
Volume: 14
Issue: 4
Author(s): Jeffry L. Dean and Karen E. Knudsen
Affiliation:
Keywords:
Androgen receptor, cancer progression, castrate resistant, hormone, metastasis, p53, prostate, retinoblastoma, tumor
suppressor
Abstract: Androgen receptor activity is essential for prostate cancer development and progression. While there are classically
defined roles for the retinoblastoma (Rb) and p53 tumor suppressor pathways in maintenance of cell cycle control
and the DNA damage response, recent studies have demonstrated a direct role of these two pathways in regulating AR expression
and function. While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms
underlying prostate cancer initiation and progression, emerging roles for Rb and p53 are likely to further expand
upon our understanding of tumor suppressor/nuclear receptor interaction. As disconnecting mitogenic signaling from ARmediated
gene transcription underlies the progression to castrate resistant prostate cancer (CRPC), functional inactivation
of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated
and AR-mediated gene transcription can become aberrant. Importantly, recent advances in small molecule inhibitor design
and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the
function of deregulated wild-type Rb and p53 protein. While such agents have undergone extensive study in many solid
tumor types, the additional importance of Rb and p53 in restraining transcription of the AR gene within the prostate provides
impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers
to CRPC. As will be reviewed in this article, restoration of Rb and p53 functions are not only important in regard to shortterm
cell cycle regulation and response to genomic stresses, but likely have direct implications for deregulation of the AR
locus.
