Androgen receptors beyond prostate cancer: an old marker as a new target

Muñoz, Javier; Wheler, Jennifer J.; Kurzrock, Razelle

doi:10.18632/oncotarget.2831

Cited by 32 publications

(26 citation statements)

References 54 publications

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“…AR binds to its native ligand, 5α-dihydrotestosterone (DHT), with strong affinity in the nucleus. AR dimers bind to androgen response elements (AREs) in the promoter region of target genes [ 4 ]. AR has biological actions in both health and disease and participates in both normal physiological processes and pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

Nanog interaction with the androgen receptor signaling axis induce ovarian cancer stem cell regulation: studies based on the CRISPR/Cas9 system

et al. 2018

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BackgroundOvarian cancer stem cells (OCSCs) contribute to the poor prognosis of ovarian cancer. Involvement of the androgen receptor (AR) in the malignant behaviors of other tumors has been reported. However, whether AR associates with Nanog (a stem cell marker) and participates in OCSC functions remain unclear. In this study, we investigated the interaction of Nanog with AR and examined whether this interaction induced stem-like properties in ovarian cancer cells.MethodsAR and Nanog expression in ovarian tumors was evaluated. Using the CRISPR/Cas9 system, we constructed a Nanog green fluorescent protein (GFP) marker cell model to investigate the expression and co-localization of Nanog and AR. Then, we examined the effect of androgen on the Nanog promoter in ovarian cancer cell lines (A2780 and SKOV3). After androgen or anti-androgen treatment, cell proliferation, migration, sphere formation, colony formation and tumorigenesis were assessed in vitro and in vivo.ResultsBoth AR and Nanog expression were obviously high in ovarian tumors. Our results showed that Nanog expression was correlated with AR expression. The androgen 5α-dihydrotestosterone (DHT) activated Nanog promoter transcription. Meanwhile, Nanog GFP-positive cells treated with DHT exhibited higher levels of proliferation, migration, sphere formation and colony formation. We also observed that the tumorigenesis of Nanog GFP-positive cells was significantly higher than that of the GFP-negative cells. Xenografts of Nanog GFP-positive cells showed significant differences when treated with androgen or anti-androgen drugs in vivo.ConclusionsThe interaction of Nanog with the AR signaling axis might induce or contribute to OCSC regulation. In addition, androgen might promote stemness characteristics in ovarian cancer cells by activating the Nanog promoter. This finding merits further study because it may provide a new understanding of OCSC regulation from a hormone perspective and lead to the reevaluation of stem cell therapy for ovarian cancer.Electronic supplementary materialThe online version of this article (10.1186/s13048-018-0403-2) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Nanog interaction with the androgen receptor signaling axis induce ovarian cancer stem cell regulation: studies based on the CRISPR/Cas9 system

et al. 2018

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“…In addition to these more conventional approaches, there is growing interest in androgen antagonism in gynecologic cancer treatment. Although androgen antagonism was historically limited to prostate cancer treatment, the development of more effective second-generation drugs has expanded the potential reach of this approach to other tumor types 13. Recent studies in endometrial carcinoma have shown some benefit to androgen antagonisms in androgen receptor-positive endometrial carcinoma primaries and metastases,11 12 and androgen antagonism has also been suggested as a therapeutic option for serous ovarian carcinomas expressing androgen receptor 21 22.…”

Section: Discussionmentioning

confidence: 99%

Emerging biomarkers in ovarian granulosa cell tumors

Mills

Chinn

Rauh

et al. 2019

International Journal of Gynecological Cancer

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ObjectiveAlthough the majority of ovarian granulosa cell tumors can be successfully managed with surgery, a subset require chemotherapy for residual and recurrent disease. The benefit of chemotherapy in this population, however, remains controversial. There is therefore interest in the development of more tolerable and effective treatment options for advanced ovarian granulosa cell tumors. We report the use of immunohistochemistry to investigate how biomarkers could inform clinical trials in granulosa cell tumors with an emphasis on emerging androgen antagonistic, immunotherapeutic, and anti-angiogenic approaches.MethodsImmunohistochemistry for androgen receptor, the immune markers programmed cell death ligand 1, indoleamine-2,3 dioxygenase, and cluster of differentiation 8, and the vascular marker cluster of differentiation 31 were evaluated on formalin-fixed paraffin-embedded whole tissue sections from 29 cases of adult-type granulosa cell tumors. Results were evaluated with clinicopathologic variables including recurrence.Results59% of granulosa cell tumors were androgen receptor-positive, suggesting a potential role for anti-androgen therapy in this tumor type. In contrast, the targetable immune modulatory molecules programmed cell death ligand 1 and indoleamine-2,3 dioxygenase were scarcely expressed, with no cases showing tumorous programmed cell death ligand 1 and a single case demonstrating very focal tumorous indoleamine-2,3 dioxygenase staining. A minority of cases expressed programmed cell death ligand 1 in occasional tumor-associated macrophages and indoleamine-2,3 dioxygenase in peritumoral vessels. Tumor-infiltrating cytotoxic T cells were also scarce in granulosa cell tumors, arguing against a significant role for immunotherapy in the absence of additional immunostimulation. Cluster of differentiation 31 immunostaining revealed a range of vascular densities across granulosa cell tumors, and future studies evaluating the role of vascular density as a predictor of response to angiogenesis inhibition are warranted. None of the biomarkers investigated were significantly correlated with recurrence, and the only clinicopathologic feature significantly correlated with outcome was stage at presentation.ConclusionsBiomarker data suggest that many ovarian granulosa cell tumors could be candidates for anti-androgen therapy, while the potential role for immunotherapy appears more limited. Vascular density could be useful for identifying optimal candidates for angiogenesis inhibition. Incorporation of these biomarkers into clinical trials could help optimize patient selection.

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“…Despite mounting evidence that AR participates in the tumorigenesis and/or progression of diverse tumors, the mechanisms of how AR signaling contributes to carcinogenesis are poorly understood [ 10 ]. Most prostate cancer cells express androgen receptor and androgen signaling plays a major role in the proliferation of prostate cancer cells [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Barboro et al reported that a high percentage of AR-positive cells is associated with a good prognosis in prostate cancer patients [ 8 ], however there are conflicting results and the prognostic value of AR expression in prostate cancer and its clinical relevance is still debated [ 9 ]. Besides prostate cancer, AR expression has been described in a wide range of solid tumors including sarcomas, melanomas and carcinomas [ 10 ]. High AR expression is associated with lower recurrence rates and better prognosis in bladder cancer [ 11 ] and improved survival in serous carcinoma of the ovary [ 12 ], advanced squamous cell carcinoma of the head and neck [ 13 ], and breast cancer [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Prognostic relevance of androgen receptor expression in renal cell carcinomas

et al. 2017

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BackgroundDespite rapid discoveries in molecular biology of renal cell carcinoma (RCC) and advances in systemic targeted therapies, development of new diagnostic and therapeutic strategies is urgently needed. The androgen receptor (AR) has been shown to hold prognostic and predicitve value in several malignancies. Here, we studied a possible association between AR expression and prognosis in patients with RCCs.ResultsLow AR expression levels were associated with occurrence of distant metastasis and higher tumor stage in papillary and clear-cell RCCs. Importantly, multivariate Cox regression analyses revealed that AR is an independent prognostic factor for cancer-specific survival.Materials and MethodsThe expression of AR was measured by immunohistochemistry and assessed by digital image analysis using a tissue microarray containing tumor tissue of a large and well-documented series of RCC patients with long-term follow-up information. Chi-squared tests, Kaplan-Meier curves and Cox regression models were used to investigate the possible relationship between AR expression and clinico-pathological characteristics and patient survival.ConclusionsPatients affected by AR-positive tumors exhibit a favorable prognosis by multiple Cox regression, while loss of AR expression is related to aggressive disease. Therefore, assessing AR expression offers valuable prognostic information that could improve treatment selection for metastatic disease. Moreover, our findings highlight a potential therapeutic use of AR pharmaceuticals in patients with RCCs.

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Androgen receptors beyond prostate cancer: an old marker as a new target

Cited by 32 publications

References 54 publications

Nanog interaction with the androgen receptor signaling axis induce ovarian cancer stem cell regulation: studies based on the CRISPR/Cas9 system

Nanog interaction with the androgen receptor signaling axis induce ovarian cancer stem cell regulation: studies based on the CRISPR/Cas9 system

Emerging biomarkers in ovarian granulosa cell tumors

Prognostic relevance of androgen receptor expression in renal cell carcinomas

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