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- Author: Wilbert Zwart x
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Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Amsterdam, the Netherlands
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Male breast cancer is a rare disease, of which little is known. In contrast to female breast cancer, the very vast majority of all cases are positive for estrogen receptor alpha (ERα), implicating the function of this steroid hormone receptor in tumor development and progression. Consequently, adjuvant treatment of male breast cancer revolves around inhibition of ERα. In addition, the androgen receptor (AR) gradually receives more attention as a relevant novel target in breast cancer treatment. Importantly, the rationale of treatment decision making is strongly based on parallels with female breast cancer. Yet, prognostic indicators are not necessarily the same in breast cancer between both genders, complicating translatability of knowledge developed in female breast cancer toward male patients. Even though ERα and AR are expressed both in female and male disease, are the genomic functions of both steroid hormone receptors conserved between genders? Recent studies have reported on mutational and epigenetic similarities and differences between male and female breast cancer, further suggesting that some features are strongly conserved between the two diseases, whereas others are not. This review critically discusses the recent developments in the study of male breast cancer in relation to ERα and AR action and highlights the potential future studies to further elucidate the genomic regulation of this rare disease.
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Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Department of Biomedical Engineering, Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
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The androgen receptor (AR) is commonly known as a key transcription factor in prostate cancer development, progression and therapy resistance. Genome-wide chromatin association studies revealed that transcriptional regulation by AR mainly depends on binding to distal regulatory enhancer elements that control gene expression through chromatin looping to gene promoters. Changes in the chromatin epigenetic landscape and DNA sequence can locally alter AR-DNA-binding capacity and consequently impact transcriptional output and disease outcome. The vast majority of reports describing AR chromatin interactions have been limited to cell lines, identifying numerous other factors and interacting transcription factors that impact AR chromatin interactions. Do these factors also impact AR cistromics – the genome-wide chromatin-binding landscape of AR – in vivo? Recent technological advances now enable researchers to identify AR chromatin-binding sites and their target genes in human specimens. In this review, we provide an overview of the different factors that influence AR chromatin binding in prostate cancer specimens, which is complemented with knowledge from cell line studies. Finally, we discuss novel perspectives on studying AR cistromics in clinical samples.
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Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands
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Glucocorticoid receptor (GR) is a key homeostatic regulator involved in governing immune response, neuro-integration, metabolism and lung function. In conjunction with its pivotal role in human biology, GR action is critically linked to the pathology of various disease types, including cancer. While pharmacological activation of GR has been used for the treatment of various liquid cancers, its role in solid cancers is less clearly defined and seems to be cancer-type dependent. This review focuses on the molecular aspects of GR biology, spanning the structural and functional basis of response to glucocorticoids, as well as how this transcription factor operates in cancer, including the implications in disease development, progression and drug resistance.
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Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
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The androgen receptor drives the growth of metastatic castration-resistant prostate cancer. This has led to the development of multiple novel drugs targeting this hormone-regulated transcription factor, such as enzalutamide – a potent androgen receptor antagonist. Despite the plethora of possible treatment options, the absolute survival benefit of each treatment separately is limited to a few months. Therefore, current research efforts are directed to determine the optimal sequence of therapies, discover novel drugs effective in metastatic castration-resistant prostate cancer and define patient subpopulations that ultimately benefit from these treatments. Molecular studies provide evidence on which pathways mediate treatment resistance and may lead to improved treatment for metastatic castration-resistant prostate cancer. This review provides, firstly a concise overview of the clinical development, use and effectiveness of enzalutamide in the treatment of advanced prostate cancer, secondly it describes translational research addressing enzalutamide response vs resistance and lastly highlights novel potential treatment strategies in the enzalutamide-resistant setting.
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Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands
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Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
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Prostate cancer development and progression is largely dependent on androgen receptor (AR) signaling. AR is a hormone-dependent transcription factor, which binds to thousands of sites throughout the human genome to regulate expression of directly responsive genes, including pro-survival genes that enable tumor cells to cope with increased cellular stress. ERN1 and XBP1 – two key players of the unfolded protein response (UPR) – are among such stress-associated genes. Here, we show that XBP1 levels in primary prostate cancer are associated with biochemical recurrence in five independent cohorts. Patients who received AR-targeted therapies had significantly lower XBP1 expression, whereas expression of the active form of XBP1 (XBP1s) was elevated. In vitro results show that AR-induced ERN1 expression led to increased XBP1s mRNA and protein levels. Furthermore, ChIP-seq analysis revealed that XBP1s binds enhancers upon stress stimuli regulating genes involved in UPR processes, eIF2 signaling and protein ubiquitination. We further demonstrate genomic overlap of AR- and XBP1s-binding sites, suggesting genomic conversion of the two signaling cascades. Transcriptomic effects of XBP1 were further studied by knockdown experiments, which lead to decreased expression of androgen-responsive genes and UPR genes. These results suggest a two-step mechanism of gene regulation, which involves androgen-induced expression of ERN1, thereby enhancing XBP1 splicing and transcriptional activity. This signaling cascade may prepare the cells for the increased protein folding, mRNA decay and translation that accompanies AR-regulated tumor cell proliferation.