Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

• Published in: The Journal of clinical investigation Vol. 123; no. 1; pp. 493 - 508
• Main Authors: Augello, Michael A, Burd, Craig J, Birbe, Ruth, McNair, Christopher, Ertel, Adam, Magee, Michael S, Frigo, Daniel E, Wilder-Romans, Kari, Shilkrut, Mark, Han, Sumin, Jernigan, Danielle L, Dean, Jeffry L, Fatatis, Alessandro, McDonnell, Donald P, Visakorpi, Tapio, Feng, Felix Y, Knudsen, Karen E
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.01.2013
• Subjects: Alternative Splicing - genetics; Androgens; Animals; Biomedical research; Cell cycle; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin-dependent kinases; Gene Expression Regulation, Neoplastic - genetics; Genes; Genetic transcription; Humans; Kinases; Male; Metastasis; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Phase transitions; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction; Snail Family Transcription Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation - genetics; Transplantation, Heterologous; Tumors; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI64750

Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying cyclin D1b function remain poorly understood. Herein, cell and human tumor xenograft models of prostate cancer were utilized to resolve the downstream pathways that are required for the protumorigenic functions of cyclin D1b. Specifically, cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b-mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. In vivo analyses provided strong evidence that Slug enhances both tumor growth and metastatic phenotypes. Collectively, these findings reveal the underpinning mechanisms behind the protumorigenic functions of cyclin D1b and demonstrate that the convergence of the cyclin D1b/AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes.