Special Issue "AR Signaling in Human Malignancies: Prostate Cancer and Beyond"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 November 2016)

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A printed edition of this Special Issue is available here.

Special Issue Editor

Guest Editor
Assoc. Prof. Dr. Emmanuel S. Antonarakis

Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRB1-1M45, Baltimore, MD 21231, USA
Website | E-Mail
Interests: prostate cancer clinical trials; prostate cancer biomarker development; AR-V7 biomarker; androgen receptor-targeted therapy; immunotherapy

Special Issue Information

Dear Colleagues,

Androgens and androgen receptor (AR) signaling are the hallmark of prostate cancer oncogenesis and disease progression, and this concept is generally well accepted. What more poorly understood is the role of AR signaling in other human malignancies. This Special Issue of Cancers will initially review the role of AR in advanced prostate cancer, and will then explore the potential role for AR signaling in other epithelial cancers. The first few articles will focus on the use of novel AR-targeting therapies in castration-resistant prostate cancer and the mechanisms of resistance to novel antiandrogens, and will also review the interaction between AR and PARP in prostate cancer, as well as the interplay between AR and BET bromodomain proteins in prostate cancer. The next several articles will review the possible role of androgens and AR signaling in breast cancer, bladder cancer, endometrial and ovarian cancers, hepatocellular and pancreatic cancers, and salivary gland cancers, as well as the potential therapeutic implications of using antiandrogen therapies in these non-prostatic malignancies. Research articles on AR signaling are also most welcome.

Assoc. Prof. Dr. Emmanuel S. Antonarakis
Guest Editor

Manuscript Submission Information

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Keywords

  • AR signaling
  • AR/PARP interplay
  • AR/BET interplay
  • prostate cancer
  • breast cancer
  • endometrial cancer
  • ovarian cancer
  • hepatocellular cancer
  • pancreatic cancer
  • salivary gland cancer

Published Papers (14 papers)

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Editorial

Jump to: Research, Review, Other

Open AccessEditorial AR Signaling in Human Malignancies: Prostate Cancer and Beyond
Received: 17 January 2018 / Revised: 17 January 2018 / Accepted: 17 January 2018 / Published: 18 January 2018
Cited by 2 | PDF Full-text (140 KB) | HTML Full-text | XML Full-text
Abstract
The notion that androgens and androgen receptor (AR) signaling are the hallmarks of prostate cancer oncogenesis and disease progression is generally well accepted. What is more poorly understood is the role of AR signaling in other human malignancies. This special issue of Cancers [...] Read more.
The notion that androgens and androgen receptor (AR) signaling are the hallmarks of prostate cancer oncogenesis and disease progression is generally well accepted. What is more poorly understood is the role of AR signaling in other human malignancies. This special issue of Cancers initially reviews the role of AR in advanced prostate cancer, and then explores the potential importance of AR signaling in other epithelial malignancies. The first few articles focus on the use of novel AR-targeting therapies in castration-resistant prostate cancer and the mechanisms of resistance to novel antiandrogens, and they also outline the interaction between AR and other cellular pathways, including PI3 kinase signaling, transcriptional regulation, angiogenesis, stromal factors, Wnt signaling, and epigenetic regulation in prostate cancer. The next several articles review the possible role of androgens and AR signaling in breast cancer, bladder cancer, salivary gland cancer, and hepatocellular carcinoma, as well as the potential treatment implications of using antiandrogen therapies in these non-prostatic malignancies. Full article

Research

Jump to: Editorial, Review, Other

Open AccessArticle Expression and Clinical Significance of Androgen Receptor in Triple-Negative Breast Cancer
Received: 10 November 2016 / Revised: 2 January 2017 / Accepted: 4 January 2017 / Published: 6 January 2017
Cited by 8 | PDF Full-text (760 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Triple-negative breast cancer (TNBC) has a poor prognosis because of frequent recurrence. Androgen receptor (AR) is involved in the pathogenesis of breast cancer, but its role is not clearly defined. The aim of this study was to explore the expression of AR [...] Read more.
Background: Triple-negative breast cancer (TNBC) has a poor prognosis because of frequent recurrence. Androgen receptor (AR) is involved in the pathogenesis of breast cancer, but its role is not clearly defined. The aim of this study was to explore the expression of AR and its relationship with clinicopathologic features in TNBC. Methods: This study investigated 1036 cases of sporadic invasive breast carcinoma. Immunohistochemical assays were performed to determine the expression of AR in 190 TNBC samples. The relationships between AR expression and clinicopathologic data and prognosis were analyzed. Results: In 190 TNBC cases, the prognosis of AR-positive patients was significantly better (p = 0.019, log-rank) than AR-negative patients, and in multivariate analysis, AR expression was an independent indicator of good prognosis (p = 0.039, hazard ratio = 0.36). In patients with disease relapse, AR positivity was significantly correlated with better prognosis (p = 0.034, log-rank). Conclusions: AR expression may be useful as a subclassification marker for prognosis in TNBC. Full article
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Review

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Open AccessReview AR Signaling and the PI3K Pathway in Prostate Cancer
Received: 27 February 2017 / Revised: 4 April 2017 / Accepted: 11 April 2017 / Published: 15 April 2017
Cited by 14 | PDF Full-text (399 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer is a leading cause of cancer-related death in men worldwide. Aberrant signaling in the androgen pathway is critical in the development and progression of prostate cancer. Despite ongoing reliance on androgen receptor (AR) signaling in castrate resistant disease, in addition to [...] Read more.
Prostate cancer is a leading cause of cancer-related death in men worldwide. Aberrant signaling in the androgen pathway is critical in the development and progression of prostate cancer. Despite ongoing reliance on androgen receptor (AR) signaling in castrate resistant disease, in addition to the development of potent androgen targeting drugs, patients invariably develop treatment resistance. Interactions between the AR and PI3K pathways may be a mechanism of treatment resistance and inhibitors of this pathway have been developed with variable success. Herein we outline the role of the PI3K pathway in prostate cancer and, in particular, its association with androgen receptor signaling in the pathogenesis and evolution of prostate cancer, as well as a review of the clinical utility of PI3K targeting. Full article
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Open AccessReview The Androgen Receptor and VEGF: Mechanisms of Androgen-Regulated Angiogenesis in Prostate Cancer
Received: 31 January 2017 / Revised: 25 March 2017 / Accepted: 4 April 2017 / Published: 10 April 2017
Cited by 12 | PDF Full-text (746 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer progression is controlled by the androgen receptor and new blood vessel formation, or angiogenesis, which promotes metastatic prostate cancer growth. Angiogenesis is induced by elevated expression of vascular endothelial growth factor (VEGF). VEGF is regulated by many factors in the tumor [...] Read more.
Prostate cancer progression is controlled by the androgen receptor and new blood vessel formation, or angiogenesis, which promotes metastatic prostate cancer growth. Angiogenesis is induced by elevated expression of vascular endothelial growth factor (VEGF). VEGF is regulated by many factors in the tumor microenvironment including lowered oxygen levels and elevated androgens. Here we review evidence delineating hormone mediated mechanisms of VEGF regulation, including novel interactions between the androgen receptor (AR), epigenetic and zinc-finger transcription factors, AR variants and the hypoxia factor, HIF-1. The relevance of describing the impact of both hormones and hypoxia on VEGF expression and angiogenesis is revealed in recent reports of clinical therapies targeting both VEGF and AR signaling pathways. A better understanding of the complexities of VEGF expression could lead to improved targeting and increased survival time for a subset of patients with metastatic castration-resistant prostate cancer. Full article
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Open AccessReview Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer
Received: 28 November 2016 / Revised: 21 February 2017 / Accepted: 21 February 2017 / Published: 28 February 2017
Cited by 11 | PDF Full-text (513 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer is the second leading cause of death from cancer among males in Western countries. It is also the most commonly diagnosed male cancer in Japan. The progression of prostate cancer is mainly influenced by androgens and the androgen receptor (AR). Androgen [...] Read more.
Prostate cancer is the second leading cause of death from cancer among males in Western countries. It is also the most commonly diagnosed male cancer in Japan. The progression of prostate cancer is mainly influenced by androgens and the androgen receptor (AR). Androgen deprivation therapy is an established therapy for advanced prostate cancer; however, prostate cancers frequently develop resistance to low testosterone levels and progress to the fatal stage called castration-resistant prostate cancer (CRPC). Surprisingly, AR and the AR signaling pathway are still activated in most CRPC cases. To overcome this problem, abiraterone acetate and enzalutamide were introduced for the treatment of CRPC. Despite the impact of these drugs on prolonged survival, CRPC acquires further resistance to keep the AR pathway activated. Functional molecular studies have shown that some of the AR collaborative transcription factors (TFs), including octamer transcription factor (OCT1), GATA binding protein 2 (GATA2) and forkhead box A1 (FOXA1), still stimulate AR activity in the castration-resistant state. Therefore, elucidating the crosstalk between the AR and collaborative TFs on the AR pathway is critical for developing new strategies for the treatment of CRPC. Recently, many compounds targeting this pathway have been developed for treating CRPC. In this review, we summarize the AR signaling pathway in terms of AR collaborators and focus on pyrrole-imidazole (PI) polyamide as a candidate compound for the treatment of prostate cancer. Full article
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Open AccessReview AR Signaling in Breast Cancer
Received: 5 December 2016 / Revised: 13 February 2017 / Accepted: 18 February 2017 / Published: 24 February 2017
Cited by 20 | PDF Full-text (1208 KB) | HTML Full-text | XML Full-text
Abstract
Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and [...] Read more.
Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies. Full article
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Open AccessReview Androgen Receptor Signaling in Bladder Cancer
Received: 1 December 2016 / Revised: 24 January 2017 / Accepted: 16 February 2017 / Published: 22 February 2017
Cited by 5 | PDF Full-text (483 KB) | HTML Full-text | XML Full-text
Abstract
Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific [...] Read more.
Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer. Full article
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Open AccessReview Androgen Receptor Signaling in Salivary Gland Cancer
Received: 22 December 2016 / Revised: 28 January 2017 / Accepted: 3 February 2017 / Published: 8 February 2017
Cited by 11 | PDF Full-text (348 KB) | HTML Full-text | XML Full-text
Abstract
Salivary gland cancers comprise a small subset of human malignancies, and are classified into multiple subtypes that exhibit diverse histology, molecular biology and clinical presentation. Local disease is potentially curable with surgery, which may be combined with adjuvant radiotherapy. However, metastatic or unresectable [...] Read more.
Salivary gland cancers comprise a small subset of human malignancies, and are classified into multiple subtypes that exhibit diverse histology, molecular biology and clinical presentation. Local disease is potentially curable with surgery, which may be combined with adjuvant radiotherapy. However, metastatic or unresectable tumors rarely respond to chemotherapy and carry a poorer prognosis. Recent molecular studies have shown evidence of androgen receptor signaling in several types of salivary gland cancer, mainly salivary duct carcinoma. Successful treatment with anti-androgen therapy in other androgen receptor-positive malignancies such as prostate and breast cancer has inspired researchers to investigate this treatment in salivary gland cancer as well. In this review, we describe the prevalence, biology, and therapeutic implications of androgen receptor signaling in salivary gland cancer. Full article
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Open AccessReview A Tale of Two Signals: AR and WNT in Development and Tumorigenesis of Prostate and Mammary Gland
Received: 6 December 2016 / Revised: 19 January 2017 / Accepted: 24 January 2017 / Published: 27 January 2017
Cited by 5 | PDF Full-text (2049 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer (PCa) is one of the most common cancers and among the leading causes of cancer deaths for men in industrialized countries. It has long been recognized that the prostate is an androgen-dependent organ and PCa is an androgen-dependent disease. Androgen action [...] Read more.
Prostate cancer (PCa) is one of the most common cancers and among the leading causes of cancer deaths for men in industrialized countries. It has long been recognized that the prostate is an androgen-dependent organ and PCa is an androgen-dependent disease. Androgen action is mediated by the androgen receptor (AR). Androgen deprivation therapy (ADT) is the standard treatment for metastatic PCa. However, almost all advanced PCa cases progress to castration-resistant prostate cancer (CRPC) after a period of ADT. A variety of mechanisms of progression from androgen-dependent PCa to CRPC under ADT have been postulated, but it remains largely unclear as to when and how castration resistance arises within prostate tumors. In addition, AR signaling may be modulated by extracellular factors among which are the cysteine-rich glycoproteins WNTs. The WNTs are capable of signaling through several pathways, the best-characterized being the canonical WNT/β-catenin/TCF-mediated canonical pathway. Recent studies from sequencing PCa genomes revealed that CRPC cells frequently harbor mutations in major components of the WNT/β-catenin pathway. Moreover, the finding of an interaction between β-catenin and AR suggests a possible mechanism of cross talk between WNT and androgen/AR signaling pathways. In this review, we discuss the current knowledge of both AR and WNT pathways in prostate development and tumorigenesis, and their interaction during development of CRPC. We also review the possible therapeutic application of drugs that target both AR and WNT/β-catenin pathways. Finally, we extend our review of AR and WNT signaling to the mammary gland system and breast cancer. We highlight that the role of AR signaling and its interaction with WNT signaling in these two hormone-related cancer types are highly context-dependent. Full article
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Open AccessReview Stromal Androgen Receptor in Prostate Cancer Development and Progression
Received: 30 November 2016 / Revised: 13 January 2017 / Accepted: 16 January 2017 / Published: 22 January 2017
Cited by 11 | PDF Full-text (2226 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, [...] Read more.
Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, it has been becoming increasingly apparent that changes in AR signalling in the surrounding stroma can dramatically influence tumour cell behavior. This is reflected in the consistent finding of a strong association between stromal AR expression and patient outcomes. In this review, we explore the relationship between AR signalling in fibroblasts/myofibroblasts and prostate cancer cells in the primary site, and detail the known functions, actions, and mechanisms of fibroblast AR signaling. We conclude with an evidence-based summary of how androgen action in stroma dramatically influences disease progression. Full article
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Open AccessReview Epigenomic Regulation of Androgen Receptor Signaling: Potential Role in Prostate Cancer Therapy
Received: 30 November 2016 / Revised: 2 January 2017 / Accepted: 11 January 2017 / Published: 16 January 2017
Cited by 6 | PDF Full-text (1343 KB) | HTML Full-text | XML Full-text
Abstract
Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, [...] Read more.
Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome. This has permitted better understanding of the underlying regulatory mechanisms of AR during carcinogenesis and revealed the importance of epigenetic modifiers. In screening for new epigenomic modifiying drugs, we identified SD-70, and found that this demethylase inhibitor is effective in CRPC cells in combination with current therapies. The aim of this review is to explore the role of epigenetic modifications as biomarkers for detection, prognosis, and risk evaluation of PCa. Furthermore, we also provide an update of the recent findings on the epigenetic key processes (DNA methylation, chromatin modifications and alterations in noncoding RNA profiles) involved in AR expression and their possible role as therapeutic targets. Full article
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Open AccessReview AR-Signaling in Human Malignancies: Prostate Cancer and Beyond
Received: 29 November 2016 / Revised: 4 January 2017 / Accepted: 5 January 2017 / Published: 11 January 2017
Cited by 12 | PDF Full-text (263 KB) | HTML Full-text | XML Full-text
Abstract
In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of [...] Read more.
In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types. Full article
Open AccessReview Androgen Receptor: A Complex Therapeutic Target for Breast Cancer
Cancers 2016, 8(12), 108; https://doi.org/10.3390/cancers8120108
Received: 28 September 2016 / Revised: 1 November 2016 / Accepted: 23 November 2016 / Published: 2 December 2016
Cited by 18 | PDF Full-text (884 KB) | HTML Full-text | XML Full-text
Abstract
Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER) and human epidermal growth factor receptor (HER2) are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR) is evolving as a molecular target [...] Read more.
Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER) and human epidermal growth factor receptor (HER2) are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR) is evolving as a molecular target for cancers that have developed resistance to conventional treatments. The high expression of AR in breast cancer and recent discovery and development of new nonsteroidal drugs targeting the AR provide a strong rationale for exploring it again as a therapeutic target in this disease. Ironically, both nonsteroidal agonists and antagonists for the AR are undergoing clinical trials, making AR a complicated target to understand in breast cancer. This review provides a detailed account of AR’s therapeutic role in breast cancer. Full article
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Other

Open AccessBrief Report Androgen Receptor Could Be a Potential Therapeutic Target in Patients with Advanced Hepatocellular Carcinoma
Received: 27 February 2017 / Revised: 2 May 2017 / Accepted: 3 May 2017 / Published: 5 May 2017
Cited by 2 | PDF Full-text (380 KB) | HTML Full-text | XML Full-text
Abstract
Hepatocellular carcinoma (HCC) is a male-dominant disease with poor prognosis. Sorafenib is the only approved systemic chemotherapeutic drug for patients with advanced HCC. Previous studies have shown that androgen and androgen receptor (AR) are involved in human hepatocarcinogenesis and the development of HCC. [...] Read more.
Hepatocellular carcinoma (HCC) is a male-dominant disease with poor prognosis. Sorafenib is the only approved systemic chemotherapeutic drug for patients with advanced HCC. Previous studies have shown that androgen and androgen receptor (AR) are involved in human hepatocarcinogenesis and the development of HCC. Here, we discuss the recent data on AR and HCC, and the combination of sorafenib and inhibitors of AR for advanced-HCC patients. Androgen-dependent and androgen-independent AR activation exist in human hepatocarcinogenesis. AR could directly control hepatocarcinogenesis and regulate the innate immune system to influence HCC progression. Combination of sorafenib with AR inhibitors might represent a potential treatment for patients with advanced HCC. Full article
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