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Modulating the Activity of Androgen Receptor for Treating Breast Cancer.

ABSTRACT: The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cancer, blocking the AR could confer better prognosis to patients. These studies support the feasibility of utilizing AR modulators as anti-cancer drugs for different subtypes of breast cancer patients. Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer.

SUBMITTER: You CP

PROVIDER: S-EPMC9739178 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Modulating the Activity of Androgen Receptor for Treating Breast Cancer.

You Chan-Ping CP Tsoi Ho H Man Ellen P S EPS Leung Man-Hong MH Khoo Ui-Soon US

International journal of molecular sciences 20221205 23

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cance ...[more]

PMID: 36499670

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Project description:IntroductionDysregulated androgen receptor (AR) activity is central to various diseases, particularly prostate cancer (PCa), in which it drives tumour initiation and progression. Consequently, antagonising AR activity via anti-androgens is an indispensable treatment option for metastatic PCa. However, despite initial tumour remission, drug resistance occurs. Therefore, the AR signalling pathway has been intensively investigated. However, the role of AR protein stability in AR signalling and therapy resistance has not yet been deciphered. Therefore, this study aimed to investigate the role of AR protein changes in transactivity and assess its mechanism as a possible target in PCa.MethodsLNCaP, C4-2, and 22Rv1 cells were treated with R1881, enzalutamide, cycloheximide, and Rocaglamide. Mass spectrometry analyses were performed on LNCaP cells to identify the pathways enriched by the treatments. Western blotting was performed to investigate AR protein levels and localisation changes. Changes in AR transactivity were determined by qPCR.ResultsMass spectrometry analyses were performed on LNCaP cells to decipher the molecular mechanisms underlying androgen- and antiandrogen-induced alterations in the AR protein. Pathway analysis revealed the enrichment of proteins involved in different pathways that regulate translation. Translational and proteasome inhibitor experiments revealed that these AR protein changes were attributable to modifications in translational activity. Interestingly, the effects on AR protein levels in castration-resistant PCa (CRPC) cells C4-2 or enzalutamide-resistant cells 22Rv1 were less prominent and non-existent. This outcome was similarly observed in the alteration of AR transactivation, which was suppressed in hormone-sensitive prostate cancer (HSPC) LNCaP cells by translational inhibition, akin to the effect of enzalutamide. In contrast, treatment-resistant cell lines showed only a slight change in AR transcription.ConclusionThis study suggests that in HSPC, AR activation triggers a signalling cascade that increases AR protein levels by enhancing its translation rate, thereby amplifying AR activity. However, this mechanism appears to be dysregulated in castration-resistant PCa cells.

Dataset Information

Modulating the Activity of Androgen Receptor for Treating Breast Cancer.

Publications

Modulating the Activity of Androgen Receptor for Treating Breast Cancer.

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