About

Eric C. Bolton is an Associate Professor in the Department of Molecular and Integrative Physiology at the University of Illinois. His research primarily focuses on the regulation of prostate development and growth by hormone receptor signaling pathways, with a particular emphasis on the androgen receptor (AR). His work aims to understand how the prostate gland develops and how disruptions in hormone receptor signaling during early prostate development predispose both humans and rodents to neoplasia, a leading cause of urologic disease among men. Bolton's research addresses the role of AR signaling in prostate development, homeostasis, and neoplasia, noting that AR signaling is necessary for normal prostate function but that its disruption can lead to conditions such as benign prostatic hyperplasia and prostate cancer, the latter being the second leading cause of cancer-related deaths in men. Bolton's laboratory employs innovative organ culture systems and genetically modified mouse models alongside modern genomic and signaling pathway analyses to identify novel crosstalk between AR and growth factor signaling pathways. This research seeks to elucidate how AR controls cell proliferation and differentiation during prostate development, which may reveal key developmental events that reemerge in prostate neoplasia. His lab focuses on identifying novel molecular players in prostate development, particularly androgen-responsive genes in the embryonic urogenital sinus and prostate. They investigate how AR signaling suppresses proliferation and promotes differentiation of prostate epithelial progenitor cells, contrasting this with AR's role in stimulating proliferation in prostate cancer cells. Additionally, Bolton studies AR-mediated regulation of cellular stress responses and apoptosis in prostate epithelial cells, aiming to understand the balance between cell proliferation and programmed cell death essential for tissue homeostasis and the implications for prostate neoplasia. Furthermore, Bolton and his collaborators have demonstrated that AR signaling can be inhibited in vivo by ligand-independent, non-competitive inhibitors, using the mouse prostate as a model. Future research in his lab aims to identify the molecular targets of these inhibitors and define their roles in AR signaling. Bolton's educational background includes a B.S. from the University of Wisconsin, Eau Claire, a Ph.D. from Johns Hopkins University School of Medicine, and postdoctoral training at the University of California, San Francisco. His comprehensive research contributes to a deeper understanding of prostate biology and the molecular mechanisms underlying prostate diseases.

Research topics

• Neuroscience
• Biology
• Biophysics
• Internal medicine
• Cell biology
• Chemistry
• Medicine
• Endocrinology
• Genetics

Selected publications

• Data sets supporting_Kim et al_PNAS_2021

  Figshare · 2021-01-01

  datasetOpen access

  Source data for Kim et al., PNAS 2021 " Spontaneous seizure and memory loss in mice expressing an epileptic encephalopathy variant in the camodulin-binding domain of Kv7.2."

  PublisherDOI

• Spontaneous seizure and memory loss in mice expressing an epileptic encephalopathy variant in the calmodulin-binding domain of K _v 7.2

  Proceedings of the National Academy of Sciences · 2021 · 31 citations

  • Neuroscience
  • Internal medicine
  • Endocrinology

  -related EE.

  PublisherOA PDFDOI

• Identifying mutation hotspots reveals pathogenetic mechanisms of KCNQ2 epileptic encephalopathy

  Scientific Reports · 2020 · 65 citations

  • Biophysics
  • Biology
  • Chemistry

  7-associated EE.

  PublisherOA PDFDOI

• Correction: Androgen-Sensitized Apoptosis of HPr-1AR Human Prostate Epithelial Cells

  PLoS ONE · 2019-03-13

  erratumOpen accessSenior author

  [This corrects the article DOI: 10.1371/journal.pone.0156145.].

  PublisherOA PDFDOI

• Issue Information

  The Prostate · 2018-04-02

  paratextOpen access

  Rest of World), 6139 (Europe), 4854 (UK). Prices are exclusive of tax. Asia-Pacifi c GST, Canadian GST/HST and European VAT will be applied at the appropriate rates. For more information on current tax rates, please go to www.wileyonlinelibrary.com/tax-vat. The price includes online access to the current and all online backfi les to January 1st 2014, where available. For other pricing options, including access information and terms and conditions, please visit www.wileyonlinelibrary.

  PublisherOA PDFDOI

• The androgen receptor malignancy shift in prostate cancer

  The Prostate · 2018-02-23 · 32 citations

  review

  BACKGROUND: Androgens and the androgen receptor (AR) are necessary for the development, function, and homeostatic growth regulation of the prostate gland. However, once prostate cells are transformed, the AR is necessary for the proliferation and survival of the malignant cells. This change in AR function appears to occur in nearly every prostate cancer. We have termed this the AR malignancy shift. METHODS: In this review, we summarize the current knowledge of the AR malignancy shift, including the DNA-binding patterns that define the shift, the transcriptome changes associated with the shift, the putative drivers of the shift, and its clinical implications. RESULTS: In benign prostate epithelial cells, the AR primarily binds consensus AR binding sites. In carcinoma cells, the AR cistrome is dramatically altered, as the AR associates with FOXA1 and HOXB13 motifs, among others. This shift leads to the transcription of genes associated with a malignant phenotype. In model systems, some mutations commonly found in localized prostate cancer can alter the AR cistrome, consistent with the AR malignancy shift. Current evidence suggests that the AR malignancy shift is necessary but not sufficient for transformation of prostate epithelial cells. CONCLUSIONS: Reinterpretation of prostate cancer genomic classification systems in light of the AR malignancy shift may improve our ability to predict clinical outcomes and treat patients appropriately. Identifying and targeting the molecular factors that contribute to the AR malignancy shift is not trivial but by doing so, we may be able to develop new strategies for the treatment or prevention of prostate cancer.

  PublisherDOI

• RET-mediated glial cell line derived neurotrophic factor signaling inhibits mouse prostate development

  Development · 2017-01-01 · 6 citations

  articleOpen accessSenior author

  In humans and rodents, the prostate gland develops from the embryonic urogenital sinus (UGS). The androgen receptor (AR) is thought to control the expression of morphogenetic genes in inductive UGS mesenchyme, which promotes proliferation and cytodifferentiation of the prostatic epithelium. However, the nature of the AR-regulated morphogenetic genes and the mechanisms whereby AR controls prostate development are not understood. Glial cell line-derived neurotrophic factor (GDNF) binds GDNF family receptor-α1 (GFRα1) and signals through activation of RET tyrosine kinase. Gene disruption studies in mice have revealed essential roles for GDNF signaling in development, however its role in prostate development is unexplored. Here, we establish novel roles of GDNF signaling in mouse prostate development. Utilizing an organ culture system for prostate development and Ret mutant mice, we demonstrate that RET-mediated GDNF signaling in UGS increases proliferation of mesenchyme cells and suppresses androgen-induced proliferation and differentiation of prostate epithelial cells, inhibiting prostate development. We also identify AR as a GDNF-repressed gene and Gdnf and Gfrα1 as androgen-repressed genes in UGS, thus establishing reciprocal regulatory crosstalk between AR and GDNF signaling in prostate development.

  PublisherOA PDFDOI

• Mice lacking β-carotene-15,15’-dioxygenase exhibit reduced serum testosterone, prostatic androgen receptor signaling, and prostatic cellular proliferation

  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · 2016-09-15 · 5 citations

  article

  β-Carotene-15,15’-dioxygenase (BCO1) cleaves dietary carotenoids at the central 15,15’ double bond, most notably acting on β-carotene to yield retinal. However, Bco1 disruption also impacts diverse physiological end points independent of dietary carotenoid feeding, including expression of genes controlling androgen metabolism. Using the Bco1 −/− mouse model, we sought to probe the effects of Bco1 disruption on testicular steroidogenesis, prostatic androgen signaling, and prostatic proliferation. Male wild-type (WT) and Bco1 −/− mice were raised on carotenoid-free AIN-93G diets before euthanasia between 10 and 14 wk of age. Weights of the prostate and seminal vesicles were significantly lower in Bco1 −/− than in WT mice (−18% and −29%, respectively). Serum testosterone levels in Bco1 −/− mice were significantly reduced by 73%. Bco1 disruption significantly reduced Leydig cell number and decreased testicular mRNA expression of Hsd17b3, suggesting inhibition of testicular testosterone synthesis. Immunofluorescent staining of the androgen receptor (AR) in the dorsolateral prostate lobes of Bco1 −/− mice revealed a decrease in AR nuclear localization. Analysis of prostatic morphology suggested decreases in gland size and secretion. These findings were supported by reduced expression of the proliferation marker Ki-67 in Bco1 −/− prostates. Expression analysis of 200 prostate cancer- and androgen-related genes suggested that Bco1 loss significantly disrupted prostatic androgen receptor signaling, cell cycle progression, and proliferation. This is the first demonstration that Bco1 disruption lowers murine circulating testosterone levels and thereby reduces prostatic androgen receptor signaling and prostatic cellular proliferation, further supporting the role of this protein in processes more diverse than carotenoid cleavage.

  PublisherDOI

• Androgen-Sensitized Apoptosis of HPr-1AR Human Prostate Epithelial Cells

  PLoS ONE · 2016-05-20 · 2 citations

  articleOpen accessSenior authorCorresponding

  Androgen receptor (AR) signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells have been investigated in human and rodent adult prostate. However, the cellular stress response of human prostate epithelial cells is not well understood, though it is central to prostate health and pathology. Here, we report that androgen sensitizes HPr-1AR and RWPE-AR human prostate epithelial cells to cell stress agents and apoptotic cell death. Although 5α-dihydrotestosterone (DHT) treatment alone did not induce cell death, co-treatment of HPr-1AR cells with DHT and an apoptosis inducer, such as staurosporine (STS), TNFt, or hydrogen peroxide, synergistically increased cell death in comparison to treatment with each apoptosis inducer by itself. We found that the synergy between DHT and apoptosis inducer led to activation of the intrinsic/mitochondrial apoptotic pathway, which is supported by robust cleavage activation of caspase-9 and caspase-3. Further, the dramatic depolarization of the mitochondrial membrane potential that we observed upon co-treatment with DHT and STS is consistent with increased mitochondrial outer membrane permeabilization (MOMP) in the pro-apoptotic mechanism. Interestingly, the synergy between DHT and apoptosis inducer was abolished by AR antagonists and inhibitors of transcription and protein synthesis, suggesting that AR mediates pro-apoptotic synergy through transcriptional regulation of MOMP genes. Expression analysis revealed that pro-apoptotic genes (BCL2L11/BIM and AIFM2) were DHT-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1) were DHT-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins, such that androgen signaling sensitizes mitochondria to apoptotic signaling, thus rendering HPr-1AR more vulnerable to cell death signals. Our study offers insight into AR-mediated regulation of prostate epithelial cell death signaling.

  PublisherOA PDFDOI

• Ablation of the Carotenoid Cleavage Enzyme β‐Carotene‐15,15′‐Dioxygenase (BCO1) Reduces Serum Testosterone and Prostatic Androgen Receptor Signaling in Mice

  The FASEB Journal · 2016-04-01

  article

  β‐carotene‐15,15′‐dioxygenase (BCO1) cleaves dietary carotenoids at the central 15,15′ double bond, most notably acting on β‐carotene to yield retinal. Ablation of this gene in mice fed carotenoid‐rich diets has been shown to affect tissue carotenoid accumulation. However, Bco1 ablation also impacts diverse physiologic endpoints independent of dietary carotenoid feeding, including expression of genes controlling androgen metabolism. Using the Bco1 − / − mouse model, we sought to probe the effects of Bco1 ablation on testicular steroidogenesis, serum testosterone levels, and prostatic androgen signaling. Male wild‐type (WT) and Bco1 − / − mice were weaned and raised on carotenoid‐free, semi‐purified AIN‐93G diets before sacrifice at 10–14 weeks of age. In three independent trials, Bco1 ablation significantly and consistently decreased serum testosterone and altered prostatic homeostasis. Organ weights of the prostate (all lobes) and seminal vesicles were significantly lower in Bco1 − / − than WT mice (−18% and −29%, respectively; p<0.001). Bco1 − / − mice had significantly reduced levels of serum testosterone (−79%; p<0.05). Additionally, Bco1 ablation decreased testicular mRNA expression of Hsd17b3 (−32% p<0.01), while increasing Hsd17b2 expression (+34%, p<0.05), suggesting a possible inhibition of testosterone synthesis. Furthermore, prostatic NanoString gene expression analysis revealed that Bco1 loss significantly (p<0.005) disrupted androgen receptor signaling, cell cycle progression, and proliferation. Reduced mRNA expression (by qPCR) of the androgen‐induced gene Msmb (−30%, p<0.05) and reduced protein expression of the proliferation marker Ki67 (by immunofluorescence microscopy; −47%, p<0.001) support these findings. While BCO1 has been suggested to function in physiologic processes more diverse than carotenoid cleavage and production of vitamin A, this is the first demonstration that Bco1 ablation impacts murine prostatic proliferation and androgen receptor signaling. Support or Funding Information Funded by NIH grant PHS‐1‐R01 CA125384

  PublisherDOI

Recent grants

• NIH Grant F32DK065402

  NIH · $139k · 2006

• AR and GDNF signaling tune growth and differentiation in the developing prostate

  NIH · $119k · 2016–2017

Frequent coauthors

• Jef D. Boeke

  Institute for Systems Biology

  16 shared

• Jichao Chen

  The University of Texas MD Anderson Cancer Center

  6 shared

• Robert M. Yarrington

  University of Utah

  6 shared

• Candice Coombes

  High Throughput Biology (United States)

  4 shared

• Albert S. Mildvan

  4 shared

• Hee Jung Chung

  University of Illinois Urbana-Champaign

  4 shared

• Christina Chaivorapol

  Sana Biotechnology (United States)

  4 shared

• MATTIAS CARDELL

  Johns Hopkins Medicine

  4 shared