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Special Issue Editors

Special Issue Information

Dear Colleagues,

The relationship between hormones and cancer has a long history. It can be traced back to the 19th century when Dr. Beatson treated a breast cancer patient by ovariectomy in 1896. In 1941, Dr. Huggins performed orchidectomy and administered estrogen to a prostate cancer patient, which lead to his receipt of the Nobel Prize in 1966. In 1971, tamoxifen came into clinical use as an endocrine therapy for breast cancer. Interestingly, the clinical use of tamoxifen preceded the molecular cloning of the estrogen receptor in 1986. Now, we understand the importance of the estrogen receptors and the androgen receptor as transcription factors in the pathogenesis of breast cancer and prostate cancer. Investigations of novel mechanisms of these receptors, such as nongenomic actions or post-transcriptional modifications, are ongoing.

The estrogen receptors and the androgen receptor belong to the nuclear receptor superfamily. Several members of this superfamily are classified as steroid or other hormone receptor subfamily. In relation with malignancies, their ligands including glucocorticoids and retinoic acid are clinically used for lymphoma and leukemia. In addition, it has been suggested that nuclear receptors without corresponding steroid ligands or orphan nuclear receptors whose endogenous ligands have not been discovered are involved in the mechanism of cancer development.

This Special Issue aims to summarize the current knowledge of the nuclear hormone receptors in relationship with cancer biology. We invite experts in this field to submit original research papers or reviews on the various nuclear receptors in human cancers. A wide range of studies from basic to clinical studies are welcome.

Prof. Dr. Satoshi Inoue
Dr. Kotaro Azuma
Guest Editors

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Keywords

hormone
nuclear receptor
genetics
transcription
RNA regulation
epigenetics
protein modification
cancer
metabolomics
breast
prostate
uterus
ovary
testis
endocrine-related cancer
hormone therapy
refractory cancer
CRPC

Published Papers (2 papers)

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Research

Jump to: Review

20 pages, 4789 KiB

Open AccessArticle

Novel AR/AR-V7 and Mnk1/2 Degrader, VNPP433-3β: Molecular Mechanisms of Action and Efficacy in AR-Overexpressing Castration Resistant Prostate Cancer In Vitro and In Vivo Models

by Elizabeth Thomas, Retheesh S. Thankan, Puranik Purushottamachar, Weiliang Huang, Maureen A. Kane, Yuji Zhang, Nicholas P. Ambulos, David J. Weber and Vincent C. O. Njar

Cells 2022, 11(17), 2699; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11172699 - 30 Aug 2022

Cited by 8 | Viewed by 2367

Abstract

Prostate cancer (PCa) relies in part on AR-signaling for disease development and progression. Earlier, we developed drug candidate galeterone, which advanced through phase 2-clinical trials in treating castration-resistant PCa (CRPC). Subsequently, we designed, synthesized, and evaluated next-generation galeterone-analogs including VNPP433-3β which is potently efficacious against pre-clinical models of PCa. This study describes the mechanism of action of VNPP433-3β that promotes degradation of full-length AR (fAR) and its splice variant AR-V7 besides depleting MNK1/2 in in vitro and in vivo CRPC models that stably overexpresses fAR. VNPP433-3β directly engages AR within the cell and promotes proteasomal degradation of fAR and its splice variant AR-V7 by enhancing the interaction of AR with E3 ligases MDM2/CHIP but disrupting AR-HSP90 binding. Next, VNPP433-3β decreases phosphorylation of 4EBP1 and abates binding of eIF4E and eIF4G to 5′ cap of mRNA by depleting MNK1/2 with consequent depletion of phosphorylated eIF4E. Finally, RNA-seq demonstrates modulation of multiple pathways that synergistically contribute to PCa inhibition. Therefore, VNPP433-3β exerts its antitumor effect by imposing 1) transcriptional regulation of AR and AR-responsive oncogenes 2) translational regulation by disrupting mRNA-5′cap-dependent translation initiation, 3) reducing AR half-life through enhanced proteasomal degradation in vitro and AR-overexpressing tumor xenografts in vivo. Full article

(This article belongs to the Special Issue Mechanism of Nuclear Hormone Receptors in Cancer)

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Review

Jump to: Research

12 pages, 1698 KiB

Open AccessReview

Efp/TRIM25 and Its Related Protein, TRIM47, in Hormone-Dependent Cancers

by Kotaro Azuma and Satoshi Inoue

Cells 2022, 11(15), 2464; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11152464 - 08 Aug 2022

Cited by 2 | Viewed by 2557

Abstract

Increasing attention has been paid to the biological roles of tripartite motif-containing (TRIM) family proteins, which typically function as E3 ubiquitin ligases. Estrogen-responsive finger protein (Efp), a member of the TRIM family proteins, also known as TRIM25, was originally identified as a protein induced by estrogen and plays critical roles in promoting endocrine-related cancers, including breast cancer, endometrial cancer, and prostate cancer. The pathophysiological importance of Efp made us interested in the roles of other TRIM family proteins that share a similar structure with Efp. Based on a phylogenetic analysis of the C-terminal region of TRIM family proteins, we focused on TRIM47 as a protein belonging to the same branch as Efp. TRIM47 is a poor prognostic factor in both breast cancer and prostate cancer. Atypical lysine-27-like poly-ubiquitination was involved in the underlying mechanism causing endocrine resistance in breast cancer. We also discuss the functions of Efp and TRIM47 in other types of cancers and innate immunity by introducing substrates the are modified by poly-ubiquitination. Full article

(This article belongs to the Special Issue Mechanism of Nuclear Hormone Receptors in Cancer)

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