Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Curr Drug Targets. 2013 Apr;14(4):460-71. doi: 10.2174/1389450111314040007.
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 AR-mediated 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.
雄激素受体活性对前列腺癌的发生和发展至关重要。虽然视网膜母细胞瘤（Rb）和 p53 肿瘤抑制途径在维持细胞周期控制和 DNA 损伤反应方面具有经典定义的作用，但最近的研究表明这两条途径在调节 AR 表达和功能方面具有直接作用。虽然 Pten 失调在前列腺癌中的作用为我们提供了对前列腺癌起始和进展机制的深入了解，但 Rb 和 p53 的新兴作用可能会进一步扩展我们对肿瘤抑制/核受体相互作用的理解。由于将有丝分裂信号与 AR 介导的基因转录分离是导致去势抵抗性前列腺癌（CRPC）进展的基础，因此这两种肿瘤抑制途径的功能失活代表了 AR 蛋白水平上调和 AR 介导的基因转录异常的一种机制。重要的是，小分子抑制剂设计和发现的最新进展导致了能够靶向这两种主要途径并恢复失调野生型 Rb 和 p53 蛋白功能的药物的鉴定。虽然这些药物在许多实体肿瘤类型中进行了广泛的研究，但 Rb 和 p53 在前列腺中抑制 AR 基因转录的额外重要性为研究这两种肿瘤抑制蛋白的丧失如何促进前列腺癌向 CRPC 的转变提供了动力。正如本文所综述的，恢复 Rb 和 p53 的功能不仅对短期细胞周期调节和对基因组应激的反应很重要，而且可能对 AR 基因座的失调具有直接影响。
