Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes
Michael A. Augello, … , Felix Y. Feng, Karen E. Knudsen
Michael A. Augello, … , Felix Y. Feng, Karen E. Knudsen
Published December 21, 2012
Citation Information: J Clin Invest. 2013;123(1):493-508. https://doi.org/10.1172/JCI64750.
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Research Article Oncology

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

Abstract

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.

Authors

Michael A. Augello, Craig J. Burd, Ruth Birbe, Christopher McNair, Adam Ertel, Michael S. Magee, Daniel E. Frigo, Kari Wilder-Romans, Mark Shilkrut, Sumin Han, Danielle L. Jernigan, Jeffry L. Dean, Alessandro Fatatis, Donald P. McDonnell, Tapio Visakorpi, Felix Y. Feng, Karen E. Knudsen

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Figure 4

Cyclin D1b promotes chromosomal confirmations associated with active transcription in response to androgen.

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Cyclin D1b promotes chromosomal confirmations associated with active tra...
(A) LNCaP cells were starved of hormone for 72 hours and treated with 10 nM DHT for 3 hours. Cells were fixed, digested with the HindIII endonuclease, and ligated; total DNA was purified. Relative distance between the constant region (proximal to AROR1 of the SNAI2 gene) and 4 test regions spanning the SNAI2 gene and downstream sequences was determined using TaqMan qPCR. Top: 100 ng of purified ligated DNA was used to test individual primer sets for each test site to ensure formation of single bands specific to ligation products. Bottom: representative images of PCR products of each ligated site in the presence or absence of DHT. A control region lacking HindIII restriction sites serves as a genomic loading control. (B) LNCaP-Vec and LNCaP-D1b cells were treated as in A, and frequency of ligation is plotted as relative to ligation frequency of parental EtOH controls, after normalizing for total DNA content (control region). (C) ChIP sequencing data of AR occupancy across the cell cycle (C. McNair and K.E. Knudsen, unpublished observations) in LNCaP cells in response to 3 hours of (10 nM) DHT. AR occupancy within the SNAI2 gene is indicated by peaks, and proximal 3C test sites are designated by triangles. Error bars represent mean ± SEM. ***P < 0.001.