Cancers

Editorial

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Open AccessEditorial

AR Signaling in Human Malignancies: Prostate Cancer and Beyond

by Emmanuel S. Antonarakis

Cancers 2018, 10(1), 22; https://doi.org/10.3390/cancers10010022 - 18 Jan 2018

Cited by 17 | Viewed by 4875

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

Research

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760 KiB

Open AccessArticle

Expression and Clinical Significance of Androgen Receptor in Triple-Negative Breast Cancer

by Yuka Asano, Shinichiro Kashiwagi, Wataru Goto, Sayaka Tanaka, Tamami Morisaki, Tsutomu Takashima, Satoru Noda, Naoyoshi Onoda, Masahiko Ohsawa, Kosei Hirakawa and Masaichi Ohira

Cancers 2017, 9(1), 4; https://doi.org/10.3390/cancers9010004 - 6 Jan 2017

Cited by 61 | Viewed by 7509

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Review

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399 KiB

Open AccessReview

AR Signaling and the PI3K Pathway in Prostate Cancer

by Megan Crumbaker, Leila Khoja and Anthony M. Joshua

Cancers 2017, 9(4), 34; https://doi.org/10.3390/cancers9040034 - 15 Apr 2017

Cited by 128 | Viewed by 11040

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

The Androgen Receptor and VEGF: Mechanisms of Androgen-Regulated Angiogenesis in Prostate Cancer

by Kurtis Eisermann and Gail Fraizer

Cancers 2017, 9(4), 32; https://doi.org/10.3390/cancers9040032 - 10 Apr 2017

Cited by 64 | Viewed by 9772

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer

by Daisuke Obinata, Kenichi Takayama, Satoru Takahashi and Satoshi Inoue

Cancers 2017, 9(3), 22; https://doi.org/10.3390/cancers9030022 - 28 Feb 2017

Cited by 34 | Viewed by 8818

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

AR Signaling in Breast Cancer

by Bilal Rahim and Ruth O’Regan

Cancers 2017, 9(3), 21; https://doi.org/10.3390/cancers9030021 - 24 Feb 2017

Cited by 90 | Viewed by 12643

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

Androgen Receptor Signaling in Bladder Cancer

by Peng Li, Jinbo Chen and Hiroshi Miyamoto

Cancers 2017, 9(2), 20; https://doi.org/10.3390/cancers9020020 - 22 Feb 2017

Cited by 76 | Viewed by 13826

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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348 KiB

Open AccessReview

Androgen Receptor Signaling in Salivary Gland Cancer

by Martin G. Dalin, Philip A. Watson, Alan L. Ho and Luc G. T. Morris

Cancers 2017, 9(2), 17; https://doi.org/10.3390/cancers9020017 - 8 Feb 2017

Cited by 67 | Viewed by 8346

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

A Tale of Two Signals: AR and WNT in Development and Tumorigenesis of Prostate and Mammary Gland

by Hubert Pakula, Dongxi Xiang and Zhe Li

Cancers 2017, 9(2), 14; https://doi.org/10.3390/cancers9020014 - 27 Jan 2017

Cited by 43 | Viewed by 11079

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

Stromal Androgen Receptor in Prostate Cancer Development and Progression

by Damien A. Leach and Grant Buchanan

Cancers 2017, 9(1), 10; https://doi.org/10.3390/cancers9010010 - 22 Jan 2017

Cited by 48 | Viewed by 12950

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

Epigenomic Regulation of Androgen Receptor Signaling: Potential Role in Prostate Cancer Therapy

by Vito Cucchiara, Joy C. Yang, Vincenzo Mirone, Allen C. Gao, Michael G. Rosenfeld and Christopher P. Evans

Cancers 2017, 9(1), 9; https://doi.org/10.3390/cancers9010009 - 16 Jan 2017

Cited by 31 | Viewed by 11589

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

AR-Signaling in Human Malignancies: Prostate Cancer and Beyond

by Michael T. Schweizer and Evan Y. Yu

Cancers 2017, 9(1), 7; https://doi.org/10.3390/cancers9010007 - 11 Jan 2017

Cited by 47 | Viewed by 7305

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

Androgen Receptor: A Complex Therapeutic Target for Breast Cancer

by Ramesh Narayanan and James T. Dalton

Cancers 2016, 8(12), 108; https://doi.org/10.3390/cancers8120108 - 2 Dec 2016

Cited by 55 | Viewed by 10007

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Other

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Open AccessBrief Report

Androgen Receptor Could Be a Potential Therapeutic Target in Patients with Advanced Hepatocellular Carcinoma

by Tatsuo Kanda, Koji Takahashi, Masato Nakamura, Shingo Nakamoto, Shuang Wu, Yuki Haga, Reina Sasaki, Xia Jiang and Osamu Yokosuka

Cancers 2017, 9(5), 43; https://doi.org/10.3390/cancers9050043 - 5 May 2017

Cited by 18 | Viewed by 5727

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

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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