A Gain-of-Function Mutation in DHT Synthesis in Castration-Resistant Prostate Cancer

Chang, Kai-Hsiung; Li, Rui; Kuri, Barbara; Lotan, Yair; Roehrborn, Claus G.; Liu, Jiayan; Vessella, Robert L.; Nelson, Peter S.; Kapur, Payal; Guo, Xiao‐Feng; Mirzaei, Hamid; Auchus, Richard J.; Sharifi, Nima

doi:10.1016/j.cell.2013.07.029

Cited by 273 publications

(308 citation statements)

References 39 publications

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“…For example, androgen receptor selectively upregulates M-phase cell cycle genes to promote CRPC (67). Interestingly, a recent study found that a gain-of-function mutation in dihydrotestosterone (the most potent androgen) synthesis partially accounts for castration resistance (68). However, some other studies have challenged the androgen receptor-dependent mechanism, as castration induces the activation of many kinases (69) and increases the expression of antiapoptotic genes independently of the androgen receptor (70).…”

Section: Discussionmentioning

confidence: 96%

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Zhang¹,

Yang²,

Chen³

et al. 2015

Molecular and Cellular Biology

142

151

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f Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC). P rostate cancer is the most common malignancy and the second leading cause of cancer-related mortality among men in the United States (1). Although androgen deprivation therapy (through medical or surgical castration) is highly effective for advanced prostate cancer (1, 2), the majority of patients eventually develop resistance and progress to castration-resistant prostate cancer (CRPC). Unfortunately, most cases of CRPC are currently incurable (1). The cause of castration resistance is still not completely known. It is expected that understanding the molecular mechanisms and identifying the molecular pathways underlying the acquisition of castration resistance in prostate cancer are critical for the design of therapeutic strategies and may lead to the discovery of novel targets.The Hippo signaling pathway, originally defined by fly geneticists, plays an important role in tumorigenesis by regulating cell proliferation and apoptosis (3-7). In mammals, protein kinases Mst1/2 (mammalian sterile 20-like 1 and 2) and Lats1/2 (large tumor suppressor 1 and 2) and the adaptor proteins WW45 (WW domain-containing protein) and Mob1 (Mps one binder 1) are the Hippo core components. These proteins form complexes to regulate their activity mainly through phosphorylation. The Hippo core is tumor suppressive and exerts its function by phosphorylating and inactivating YAP (Yes-associated protein) and its paralog, TAZ (transcriptional coactivator with a PDZ-bi...

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Section: Discussionmentioning

confidence: 96%

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Zhang¹,

Yang²,

Chen³

et al. 2015

Molecular and Cellular Biology

142

151

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“…Shared resistance mechanisms involve alternative strategies to activate the AR, such as intratumor steroid biosynthesis, 57 activation of the glucocorticoid receptor 58 and emergence of an AR splice variant, such as ARV7, 59 as well as activation of non-AR survival pathways. With regard to the interaction between ASIs and docetaxel, Schweizer et al reported, in the retrospective study of 119 mCRPC patients, shorter PFS in patients (n = 24) who were treated with abiraterone followed by docetaxel compared with patients (n = 95) treated with only docetaxel (PFS of 7.6 months in docetaxel and 4.4 months in abiraterone followed by docetaxel, P = 0.003), implying the cross-resistance between ASIs and docetaxel.…”

Section: Cross-resistance Between Classes Of Agentsmentioning

confidence: 99%

Current treatment strategies for advanced prostate cancer

et al. 2017

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During the past decade, treatment strategies for patients with advanced prostate cancer involving stage IV (T4N0M0, N1M0 or M1) hormone-sensitive prostate cancer and recurrent prostate cancer after treatment with curative intent, as well as castration-resistant prostate cancer, have extensively evolved with the introduction and approval of several new agents including sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, all of which have shown significant improvement on overall survival. The appropriate use of these agents and the proper sequencing of these agents are still not optimized. The results of several recently reported randomized controlled trials and retrospective studies could assist in developing a treatment strategy for advanced prostate cancer. In addition, prospective studies and molecular characterization of tumors to address these issues are ongoing.

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“…1). Expression of the 1245C SNP results in increased HSD3B1 protein levels via inhibition of ubiquitin-mediated degradation and subsequently a greater flux toward DHT synthesis (Chang et al 2013). Heterozygous HSD3B1 variant (1245C) allele has been associated with a shorter time to CRPC in a Chinese cohort of 108 patients where the heterozygote prevalence was 17% (Wu et al 2015).…”

Section: Genomic Alterations Implicating Sex Steroids In Prostate Canmentioning

confidence: 99%

Sex steroids in the tumor microenvironment and prostate cancer progression

Boibessot¹,

Toren²

2018

Endocrine-Related Cancer

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Prostate cancer is uniquely dependent on androgens. Despite years of research on the relationship between androgens and prostate cancer, many questions remain as to the biological effects of androgens and other sex steroids during prostate cancer progression. This article reviews the clinical and basic research on the influence of sex steroids such as androgens, estrogens and progesterone within the prostate tumor microenvironment on the progression of prostate cancer. We review clinical studies to date evaluating serum sex steroids as prognostic biomarkers and discuss their respective biological effects within the prostate tumor microenvironment. We also review the link between genomic alterations and sex steroid levels within prostate tumors. Finally, we highlight the links between sex steroid levels and the function of the immune system within the tumor microenvironment. As the context of treatment of lethal prostate cancer evolves over time, an understanding of this underlying biology remains central to developing optimal treatment approaches.

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A Gain-of-Function Mutation in DHT Synthesis in Castration-Resistant Prostate Cancer

Cited by 273 publications

References 39 publications

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Current treatment strategies for advanced prostate cancer

Sex steroids in the tumor microenvironment and prostate cancer progression

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