The Hallmarks of Precancer.

Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.

Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.

One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.

Potential roles of FGF5 as a candidate therapeutic target in prostate cancer.

Fibroblast growth factor (FGF) is a secreted ligand that is widely expressed in embryonic tissues but its expression decreases with age. In the developing prostate, FGF5 has been proposed to interact with the Hedgehog (Hh) signaling pathway to guide mitogenic processes. In the adult prostate, the FGF/FGFR signaling axis has been implicated in prostate carcinogenesis, but focused studies on FGF5 functions in the prostate are limited. Functional studies completed in other cancer models point towards FGF5 overexpression as an oncogenic driver associated with stemness, metastatic potential, proliferative capacity, and increased tumor grade. In this review, we explore the significance of FGF5 as a therapeutic target in prostate cancer (PCa) and other malignancies; and we introduce a potential route of investigation to link FGF5 to benign prostatic hyperplasia (BPH). PCa and BPH are two primary contributors to the disease burden of the aging male population and have severe implications on quality of life, psychological wellbeing, and survival. The development of new FGF5 inhibitors could potentially alleviate the health burden of PCa and BPH in the aging male population.