Tissue-Selective Regulation of Androgen-Responsive Genes

Abstract

Introduction. Androgens regulate a wide array of physiological processes, including male sexual development, bone and muscle growth, and behavior and cognition. Because androgens play a vital role in so many tissues, changes in androgen signaling are associated with a plethora of diseases. How such varied responses are achieved by a single stimulus is not well understood. Androgens act primarily through the androgen receptor (AR), a hormone nuclear receptor that is expressed in a select variety of tissues. Methods. In order to gain a better understanding of how the tissue-selective effects of androgens are achieved, we performed a comparison of microarray data, using previously published datasets and several of our own microarray datasets. These datasets were derived from clinically relevant, AR-expressing tissues dissected from rodents treated with the full androgen dihydrotestosterone (DHT). Results. We found that there is a diverse response to DHT, with very little overlap of androgen regulated genes in each tissue. Gene ontology analyses also indicated that, while several tissues regulate similar biological processes in response to DHT, most androgen regulated processes are specific to one or a few tissues. Thus, it appears that the disparate physiological effects mediated by androgens begin with widely varying effects on gene expression in different androgen-sensitive tissues. Conclusion. The analysis completed in this study will lead to an improved understanding of how androgens mediate diverse, tissue-specific processes and better ways to assess the tissue-selective effects of AR modulators during drug development.

• Androgens
• Selectivity
• Microarray
• QPCR
• Gene ontology
• Prostate

ACKNOWLEDGMENTS

We gratefully acknowledge the assistance of the UCSF Functional Genomics Core Facility (Rebecca Barbeau and Andrea Barczak) in performing the microarray analyses. We thank the UCSF Preclinical Therapeutics Core Facility, especially Byron Hann, Don Hom, Donghui Wang, and Paul Phojanakong, and the City of Hope Animal Resource Center, especially Trinka Adamson, Linda Pavey, Stephanie Wright-Golightly, and Tracey Dobbs, for assistance with animal experiments. We also thank Dr. Marc Diamond and Dr. Keith Yamamoto and their lab members for critical discussions of this work. This project was supported by grant R00CA138711 (JOJ) and by Grant Number P30 CA033572 from the National Cancer Institute (City of Hope Cancer Center shared facilities). The UCSF Functional Genomics Core Facility is supported by the Sandler Asthma Basic Research (SABRE) Center Functional Genomics Core Facility and NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131.

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.