225 research outputs found
Novel androgen receptor coregulator GRHL2 exerts both oncogenic and antimetastatic functions in prostate cancer
No full textAbstract not availableSteve Paltoglou, Rajdeep Das, Scott L. Townley, Theresa E. Hickey, Gerard A. Tarulli, Isabel Coutinho, Rayzel Fernandes, Adrienne R. Hanson, Iza Denis, Jason S. Carroll, Scott M. Dehm, Ganesh V. Raj, Stephen R. Plymate, Wayne D. Tilley and Luke A. Selt
Abstract 5643: Physical and functional interactions of exon-skipping variants of androgen receptor with the full-length counterpart
No full textAbstract
The androgen receptor (AR) is arguably the critical driver of not only early but also advanced prostate cancer. The recent comprehensive splicing landscapes revealed that metastatic castration resistant prostate cancer harbors multiple forms of AR variants (AR-Vs), many of which have diverse patterns of inclusion/exclusion of exons (E4-8) corresponding to the ligand-binding domain. We had used AR-negative M12 prostate cancer cell line and recently reported characteristics of AR-Vs with respect to their subcellular localization and transcriptional activation on luciferase reporter driven by probasin-based promoter (AR2PB-luc)(1). While ARv5es is predominantly nuclear and constitutively active like well-documented ARv567es, many others are castration -induced variants are inactive. As many AR-Vs and the full-length AR (AR-FL) are co-expressed in the same cell, it is important to determine how these inactive AR-Vs interact with active AR including AR-FL. To this end, we examined two inactive AR-Vs namely v7es and v56es in relation to AR-FL. ARv7es, which skips exon 7, is predominantly localized in cytoplasm. ARv7es physically interacted with AR-FL. Moreover, nuclear accumulation of ARv7es was promoted by the addition of dihydrotestosterone (DHT) only in the presence of AR-FL, suggesting that ARv7es and AR-FL heterodimerize in the nuclear compartment. However, DHT-dependent transactivation of AR-FL was not affected by the presence of ARv7es. More specifically, in M12 cells, AR2PB-luc was transactivated by AR-FL to the similar extents either in the presence or absence of ARv7es. In addition, in doxycycline (Dox)-inducible ARv7es stable LNCaP cell line (LNCaP/ARv7es), the presence of ARv7es did not affect DHT-induced expression of endogenous PSA and NKX3.1 transcripts as well as transactivation of AR2PB-luc. In the similar setting, when we examined ARv56es which also physically interacted with AR-FL, Dox-induced expression of ARv56es in LNCaP/ARv56es was sufficient to induce expression of endogenous PSA and NKX3.1 transcripts. Further, DHT-induced expression of these transcripts was enhanced by ARv56es in LNCaP/ARv56es. Accordingly, we propose that AR-Vs display differential modes of action on AR-FL as exemplified by ARv7es as the bystander and v56es as the effector. 1. Oncogene (PMID: 27694897)
Citation Format: Takuma Uo, Cynthia C. Sprenger, Shihua Sun, Robert K. Bradley, Peter S. Nelson, Stephen R. Plymate. Physical and functional interactions of exon-skipping variants of androgen receptor with the full-length counterpart [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5643. doi:10.1158/1538-7445.AM2017-5643</jats:p
Expression of androgen receptor splice variants in clinical breast cancers
No full textPublished: November 05, 2015The importance of androgen receptor (AR) signaling is increasingly being recognized in breast cancer, which has elicited clinical trials aimed at assessing the efficacy of androgen deprivation therapy (ADT) for metastatic disease. In prostate cancer, resistance to ADT is frequently associated with the emergence of androgen-independent splice variants of the AR (AR variants, AR-Vs) that lack the LBD and are constitutively active. Women with breast cancer may be prone to a similar phenomenon. Herein, we show that in addition to the prototypical transcript, the AR gene produces a diverse range of AR-V transcripts in primary breast tumors. The most frequently and highly expressed variant was AR-V7 (exons 1/2/3/CE3), which was detectable at the mRNA level in > 50% of all breast cancers and at the protein level in a subset of ERα-negative tumors. Functionally, AR-V7 is a constitutively active and ADT-resistant transcription factor that promotes growth and regulates a transcriptional program distinct from AR in ERα-negative breast cancer cells. Importantly, we provide ex vivo evidence that AR-V7 is upregulated by the AR antagonist enzalutamide in primary breast tumors. These findings have implications for treatment response in the ongoing clinical trials of ADT in breast cancer.Theresa E. Hickey, Connie M. Irvine, Heidi Dvinge, Gerard A. Tarulli, Adrienne R. Hanson, Natalie K. Ryan, Marie A. Pickering, Stephen N. Birrell, Dong Gui Hu, Peter I. Mackenzie, Roslin Russell, Carlos Caldas, Ganesh V. Raj, Scott M. Dehm, Stephen R. Plymate, Robert K. Bradley, Wayne D. Tilley, Luke A. Selt
Inhibition of the Androgen Receptor Amino-Terminal Domain by a Small Molecule as Treatment for Castrate-Resistant Prostate Cancer
No full textSuperoxide Dismutase and Transcription Factor sox9 as Mediators of Tumor Suppression by mac25 (IGFBP-rp1) in Prostate Cancer Cells
No full textConstitutively-active androgen receptor variants function independently of the HSP90 chaperone but do not confer resistance to HSP90 inhibitors
No full textThe development of lethal, castration resistant prostate cancer is associated with adaptive changes to the androgen receptor (AR), including the emergence of mutant receptors and truncated, constitutively active AR variants. AR relies on the molecular chaperone HSP90 for its function in both normal and malignant prostate cells, but the requirement for HSP90 in environments with aberrant AR expression is largely unknown. Here, we investigated the efficacy of three HSP90 inhibitors, 17-AAG, HSP990 and AUY922, against clinically-relevant AR missense mutants and truncated variants. HSP90 inhibition effectively suppressed the signaling of wild-type AR and all AR missense mutants tested. By contrast, two truncated AR variants, AR-V7 and ARv567es, exhibited marked resistance to HSP90 inhibitors. Supporting this observation, nuclear localization of the truncated AR variants was not affected by HSP90 inhibition and AR variant:HSP90 complexes could not be detected in prostate cancer cells. Interestingly, HSP90 inhibition resulted in accumulation of AR-V7 and ARv567es in both cell lines and human tumor explants. Despite the apparent independence of AR variants from HSP90 and their treatment-associated induction, the growth of cell lines with endogenous or enforced expression of AR-V7 or ARv567es remained highly sensitive to AUY922. This study demonstrates that functional AR variant signaling does not confer resistance to HSP90 inhibition, yields insight into the interaction between AR and HSP90 and provides further impetus for the clinical application of HSP90 inhibitors in advanced prostate cancer.Joanna L. Gillis, Luke A. Selth, Margaret M. Centenera, Scott L. Townley, Shihua Sun, Stephen R. Plymate, Wayne D. Tilley and Lisa M. Butle
Inhibition of the Androgen Receptor Amino-Terminal Domain by a Small Molecule as Treatment for Castrate-Resistant Prostate Cancer
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