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Special Issue "Sex Hormone Receptor Signals in Human Malignancies"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 November 2018

Special Issue Editor

Guest Editor
Dr. Hiroshi Miyamoto

Departments of Pathology & Laboratory Medicine, Oncology, and Urology, University of Rochester Medical Center, Rochester, NY, USA
Website | E-Mail
Interests: nuclear hormone receptors; androgen receptor; glucocorticoid receptor; antiandrogens; glucocorticoids; urothelial cancer; prostate cancer; genitourinary pathology

Special Issue Information

Dear Colleagues,

Sex steroids, including androgens, estrogens, and progestogens, are known to have widespread physiological actions beyond the reproductive system via binding to the sex hormone receptors, members of the nuclear receptor superfamily that function as ligand-inducible transcription factors. Meanwhile, the roles of androgen receptor and estrogen/progesterone receptors have been widely studied in prostate and breast cancers, respectively. However, emerging evidence implies that sex hormone receptor signals play a role in the development and progression of various other types of malignancies, although their exact functions are not fully characterized. These malignancies include, but are not limited to, endometrial cancer, ovarian cancer, urothelial tumor of the bladder or upper urinary tract, liver cancer, lung cancer, and gastrointestinal cancer. Thus, the aim of this Special Issue is to provide an overview of current preclinical and clinical findings indicating the involvement of sex hormone receptor signals in human malignancies that have not traditionally been considered as endocrine neoplasms. Original research or review articles on androgen/estrogen/progesterone receptor signaling in prostate or breast cancer would also be most welcome.

Dr. Hiroshi Miyamoto
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • androgen receptor
  • estrogen receptor
  • progesterone receptor
  • prostate cancer
  • breast cancer
  • female reproductive system cancer
  • urothelial cancer
  • liver cancer
  • lung cancer
  • gastrointestinal cancer

Published Papers (4 papers)

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Research

Open AccessArticle BRCA1 Interacting Protein COBRA1 Facilitates Adaptation to Castrate-Resistant Growth Conditions
Int. J. Mol. Sci. 2018, 19(7), 2104; https://doi.org/10.3390/ijms19072104
Received: 31 May 2018 / Revised: 22 June 2018 / Accepted: 12 July 2018 / Published: 20 July 2018
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Abstract
COBRA1 (co-factor of BRCA1) is one of the four subunits of the negative elongation factor originally identified as a BRCA1-interacting protein. Here, we provide first-time evidence for the oncogenic role of COBRA1 in prostate pathogenesis. COBRA1 is aberrantly expressed in prostate tumors. It
[...] Read more.
COBRA1 (co-factor of BRCA1) is one of the four subunits of the negative elongation factor originally identified as a BRCA1-interacting protein. Here, we provide first-time evidence for the oncogenic role of COBRA1 in prostate pathogenesis. COBRA1 is aberrantly expressed in prostate tumors. It positively influences androgen receptor (AR) target gene expression and promoter activity. Depletion of COBRA1 leads to decreased cell viability, proliferation, and anchorage-independent growth in prostate cancer cell lines. Conversely, overexpression of COBRA1 significantly increases cell viability, proliferation, and anchorage-independent growth over the higher basal levels. Remarkably, AR-positive androgen dependent (LNCaP) cells overexpressing COBRA1 survive under androgen-deprivation conditions. Remarkably, treatment of prostate cancer cells with well-studied antitumorigenic agent, 2-methoxyestradiol (2-ME2), caused significant DNA methylation changes in 3255 genes including COBRA1. Furthermore, treatment of prostate cancer cells with 2-ME2 downregulates COBRA1 and inhibition of prostate tumors in TRAMP (transgenic adenocarcinomas of mouse prostate) animals with 2-ME2 was also associated with decreased COBRA1 levels. These observations implicate a novel role for COBRA1 in progression to CRPC and suggest that COBRA1 downregulation has therapeutic potential. Full article
(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)
Figures

Figure 1

Open AccessArticle A hnRNP K–AR-Related Signature Reflects Progression toward Castration-Resistant Prostate Cancer
Int. J. Mol. Sci. 2018, 19(7), 1920; https://doi.org/10.3390/ijms19071920
Received: 15 June 2018 / Revised: 27 June 2018 / Accepted: 29 June 2018 / Published: 30 June 2018
PDF Full-text (3701 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The major challenge in castration-resistant prostate cancer (CRPC) remains the ability to predict the clinical responses to improve patient selection for appropriate treatments. The finding that androgen deprivation therapy (ADT) induces alterations in the androgen receptor (AR) transcriptional program by AR coregulators activity
[...] Read more.
The major challenge in castration-resistant prostate cancer (CRPC) remains the ability to predict the clinical responses to improve patient selection for appropriate treatments. The finding that androgen deprivation therapy (ADT) induces alterations in the androgen receptor (AR) transcriptional program by AR coregulators activity in a context-dependent manner, offers the opportunity for identifying signatures discriminating different clinical states of prostate cancer (PCa) progression. Gel electrophoretic analyses combined with western blot showed that, in androgen-dependent PCa and CRPC in vitro models, the subcellular distribution of spliced and serine-phosphorylated heterogeneous nuclear ribonucleoprotein K (hnRNP K) isoforms can be associated with different AR activities. Using mass spectrometry and bioinformatic analyses, we showed that the protein sets of androgen-dependent (LNCaP) and ADT-resistant cell lines (PDB and MDB) co-immunoprecipitated with hnRNP K varied depending on the cell type, unravelling a dynamic relationship between hnRNP K and AR during PCa progression to CRPC. By comparing the interactome of LNCaP, PDB, and MDB cell lines, we identified 51 proteins differentially interacting with hnRNP K, among which KLK3, SORD, SPON2, IMPDH2, ACTN4, ATP1B1, HSPB1, and KHDRBS1 were associated with AR and differentially expressed in normal and tumor human prostate tissues. This hnRNP K–AR-related signature, associated with androgen sensitivity and PCa progression, may help clinicians to better manage patients with CRPC. Full article
(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)
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Graphical abstract

Open AccessArticle Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract
Int. J. Mol. Sci. 2018, 19(3), 777; https://doi.org/10.3390/ijms19030777
Received: 20 February 2018 / Revised: 28 February 2018 / Accepted: 6 March 2018 / Published: 8 March 2018
PDF Full-text (2759 KB) | HTML Full-text | XML Full-text
Abstract
Using preclinical models, we have recently found that ELK1, a transcriptional factor that activates downstream targets, including c-fos proto-oncogene, induces bladder cancer outgrowth. Here, we immunohistochemically determined the expression status of phospho-ELK1, an activated form of ELK1, in upper urinary tract urothelial carcinoma
[...] Read more.
Using preclinical models, we have recently found that ELK1, a transcriptional factor that activates downstream targets, including c-fos proto-oncogene, induces bladder cancer outgrowth. Here, we immunohistochemically determined the expression status of phospho-ELK1, an activated form of ELK1, in upper urinary tract urothelial carcinoma (UUTUC). Overall, phospho-ELK1 was positive in 47 (47.5%; 37 weak (1+) and 10 moderate (2+)) of 99 UUTUCs, which was significantly (P = 0.002) higher than in benign urothelium (21 (25.3%) of 83; 17 1+ and 4 2+) and was also associated with androgen receptor expression (P = 0.001). Thirteen (35.1%) of 37 non-muscle-invasive versus 34 (54.8%) of 62 muscle-invasive UUTUCs (P = 0.065) were immunoreactive for phospho-ELK1. Lymphovascular invasion was significantly (P = 0.014) more often seen in phospho-ELK1(2+) tumors (80.0%) than in phospho-ELK1(0/1+) tumors (36.0%). There were no statistically significant associations between phospho-ELK1 expression and tumor grade, presence of concurrent carcinoma in situ or hydronephrosis, or pN status. Kaplan-Meier and log-rank tests revealed that patients with phospho-ELK1(2+) tumor had marginally and significantly higher risks of disease progression (P = 0.055) and cancer-specific mortality (P = 0.008), respectively, compared to those with phospho-ELK1(0/1+) tumor. The current results thus support our previous observations in bladder cancer and further suggest that phospho-ELK1 overexpression serves as a predictor of poor prognosis in patients with UUTUC. Full article
(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)
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Open AccessArticle Sex Hormone Receptors in Benign and Malignant Salivary Gland Tumors: Prognostic and Predictive Role
Int. J. Mol. Sci. 2018, 19(2), 399; https://doi.org/10.3390/ijms19020399
Received: 21 November 2017 / Revised: 3 January 2018 / Accepted: 19 January 2018 / Published: 30 January 2018
PDF Full-text (6277 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The role of sex hormone receptors in human cancer development and progression has been well documented in numerous studies, as has the success of sex hormone antagonists in the biological therapy of many human tumors. In salivary gland tumors (SGTs), little and conflicting
[...] Read more.
The role of sex hormone receptors in human cancer development and progression has been well documented in numerous studies, as has the success of sex hormone antagonists in the biological therapy of many human tumors. In salivary gland tumors (SGTs), little and conflicting information about the role of the estrogen receptor alpha (ERα), progesterone receptor (PgR) and androgen receptor (AR) has been described and in most cases the use of sex hormone antagonists is not contemplated in clinical practice. In this study, we analyzed a panel of sex hormone receptors that have not been widely investigated in SGTs—ERα, PgR, AR, but also ERβ and GPR30—to define their expression pattern and their prognostic and predictive value in a case series of 69 benign and malignant SGTs. We showed the aberrant expression of AR in mucoepidermoid and oncocytic carcinoma, a strong relation between cytoplasmic ERβ expression and tumor grade, and a strong correlation between nuclear GPR30 expression and disease-free survival (DFS) of SGT patients. Full article
(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)
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Figure 1

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Small Molecule Targeting of the Glucocorticoid Receptor Suppresses the AR-V7 Transcriptome

Authors: David Mulholland, Lin Wang, Geoffrey Bryant, Guilhem Roubaud

Abstract: Enzalutamide resistance is postulated to correspond with elevated expression and activity of the Glucocorticoid Receptor Signaling Axis.  However, the manner in which compensatory GR function facilitates continued survival in prostate cancer cells remains unclear.  Using newly developed small molecule inhibitors, developed by Corcept Therapeutics, that selectively target the GR, we have observed marked reduction of growth potential in castration resistant prostate (CRPC) cells dependent upon the AR-V7 isoform and its defined gene signature.  We have demonstrated that mifepristone and selective Corcept inhibitors can cooperate with enzalutamide treatment to reduce growth in 22RV1 prostate cancer cells in a dose dependent and synergistic manner.  Quantitative PCR analysis demonstrated significant reductions in the ratios of AR-V7 target genes compared to AR full length (AR-FL) target genes, thereby providing a mechanism for improved growth inhibition in Enz resistant prostate cancer cells.  These data provide rationale for the clinical co-targeting of AR and GR signaling axes particularly in PC cells with AR isoform dependent progression. 

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