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Sex Hormone Receptor Signals in Human Malignancies

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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: closed (30 November 2018) | Viewed by 55286

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Special Issue Editor

Prof. Hiroshi Miyamoto

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Director of Genitourinary Pathology, University of Rochester Medical Center, Rochester, NY, USA
Interests: nuclear hormone receptors; androgen receptor; glucocorticoid receptor; antiandrogens; glucocorticoids; urothelial cancer; prostate cancer; genitourinary pathology
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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

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Keywords

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

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Published Papers (10 papers)

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Editorial

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3 pages, 159 KiB

Open AccessEditorial

Sex Hormone Receptor Signals in Human Malignancies

by Hiroshi Miyamoto

Int. J. Mol. Sci. 2019, 20(11), 2677; https://doi.org/10.3390/ijms20112677 - 31 May 2019

Cited by 2 | Viewed by 2138

Abstract

(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)

Research

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11 pages, 1447 KiB

Open AccessArticle

Molecular Insights into the Classification of Luminal Breast Cancers: The Genomic Heterogeneity of Progesterone-Negative Tumors

by Gianluca Lopez, Jole Costanza, Matteo Colleoni, Laura Fontana, Stefano Ferrero, Monica Miozzo and Nicola Fusco

Int. J. Mol. Sci. 2019, 20(3), 510; https://doi.org/10.3390/ijms20030510 - 25 Jan 2019

Cited by 28 | Viewed by 4799

Abstract

Estrogen receptor (ER)-positive progesterone receptor (PR)-negative breast cancers are infrequent but clinically challenging. Despite the volume of genomic data available on these tumors, their biology remains poorly understood. Here, we aimed to identify clinically relevant subclasses of ER+/PR− breast cancers based on their mutational landscape. The Cancer Genomics Data Server was interrogated for mutational and clinical data of all ER+ breast cancers with information on PR status from The Cancer Genome Atlas (TCGA), Memorial Sloan Kettering (MSK), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) projects. Clustering analysis was performed using gplots, ggplot2, and ComplexHeatmap packages. Comparisons between groups were performed using the Student’s t-test and the test of Equal or Given Proportions. Survival curves were built according to the Kaplan–Meier method; differences in survival were assessed with the log-rank test. A total of 3570 ER+ breast cancers (PR− n = 959, 27%; PR+ n = 2611, 73%) were analyzed. Mutations in well-known cancer genes such as TP53, GATA3, CDH1, HER2, CDH1, and BRAF were private to or enriched for in PR− tumors. Mutual exclusivity analysis revealed the presence of four molecular clusters with significantly different prognosis on the basis of PIK3CA and TP53 status. ER+/PR− breast cancers are genetically heterogeneous and encompass a variety of distinct entities in terms of prognostic and predictive information. Full article

(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)

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13 pages, 2855 KiB

Open AccessArticle

Interaction of ERα and NRF2 Impacts Survival in Ovarian Cancer Patients

by Bastian Czogalla, Maja Kahaly, Doris Mayr, Elisa Schmoeckel, Beate Niesler, Thomas Kolben, Alexander Burges, Sven Mahner, Udo Jeschke and Fabian Trillsch

Int. J. Mol. Sci. 2019, 20(1), 112; https://doi.org/10.3390/ijms20010112 - 29 Dec 2018

Cited by 28 | Viewed by 9332

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) regulates cytoprotective antioxidant processes. In this study, the prognostic potential of NRF2 and its interactions with the estrogen receptor α (ERα) in ovarian cancer cells was investigated. NRF2 and ERα protein expression in ovarian cancer tissue was analyzed as well as mRNA expression of NRF2 (NFE2L2) and ERα (ESR1) in four ovarian cancer and one benign cell line. NFE2L2 silencing was carried out to evaluate a potential interplay between NRF2 and ERα. Cytoplasmic NRF2 expression as inactive form had significantly higher expression in patients with low-grade histology (p = 0.03). In the serous cancer subtype, high cytoplasmic NRF2 expression (overall survival (OS), median 50.6 vs. 29.3 months; p = 0.04) and high ERα expression (OS, median 74.5 vs. 27.1 months; p = 0.002) was associated with longer overall survival as well as combined expression of both inactive cytoplasmic NRF2 and ERα in the whole cohort (median 74.5 vs. 37.7 months; p = 0.04). Cytoplasmic NRF2 expression showed a positive correlation with ERα expression (p = 0.004). NFE2L2 was found to be highly expressed in the ovarian cancer cell lines OVCAR3, UWB1.289, and TOV112D. Compared with the benign cell line HOSEpiC, ESR1 expression was reduced in all ovary cancer cell lines (all p < 0.001). Silencing of NFE2L2 induced a higher mRNA expression of ESR1 in the NFE2L2 downregulated cancer cell lines OVCAR3 (p = 0.003) and ES2 (p < 0.001), confirming genetic interactions of NRF2 and ERα. In this study, both inactive cytoplasmic NRF2 and high ERα expression were demonstrated to be associated with improved survival in ovarian cancer patients. Further understanding of interactions within the estradiol–ERα–NRF2 pathway could better predict the impact of endocrine therapy in ovarian cancer. Full article

(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)

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12 pages, 2915 KiB

Open AccessArticle

High Throughput Chemical Screening Reveals Multiple Regulatory Proteins on FOXA1 in Breast Cancer Cell Lines

by Shixiong Wang, Sachin Kumar Singh, Madhumohan R. Katika, Sandra Lopez-Aviles and Antoni Hurtado

Int. J. Mol. Sci. 2018, 19(12), 4123; https://doi.org/10.3390/ijms19124123 - 19 Dec 2018

Cited by 9 | Viewed by 6019

Abstract

Forkhead box A1 (FOXA1) belongs to the forkhead class transcription factor family, playing pioneering function for hormone receptors in breast and prostate cancers, and mediating activation of linage specific enhancers. Interplay between FOXA1 and breast cancer specific signaling pathways has been reported previously, indicating a regulation network on FOXA1 in breast cancer cells. Here in this study, we aimed to identify which are the proteins that could potentially control FOXA1 function in breast cancer cell lines expressing different molecular markers. We first established a luciferase reporter system reflecting FOXA1 binding to DNA. Then, we applied high throughput chemical screening of multiple protein targets and mass spectrometry in breast cancer cell lines expressing different molecular markers: ER positive/HER2 negative (MCF-7), ER positive/HER2 positive (BT474), and ER negative/HER2 positive (MDA-MB-453). Regardless of estrogen receptor status, HER2 (human epidermal growth factor receptor 2) enriched cell lines showed similar response to kinase inhibitors, indicating the control of FOXA1 by cell signaling kinases. Among these kinases, we identified additional receptor tyrosine kinases and cyclin-dependent kinases as regulators of FOXA1. Furthermore, we performed proteomics experiments from FOXA1 inmunoprecipitated protein complex to identify that FOXA1 interacts with several proteins. Among all the targets, we identified cyclin-dependent kinase 1 (CDK1) as a positive factor to interact with FOXA1 in BT474 cell line. In silico analyses confirmed that cyclin-dependent kinases might be the kinases responsible for FOXA1 phosphorylation at the Forkhead domain and the transactivation domain. These results reveal that FOXA1 is potentially regulated by multiple kinases. The cell cycle control kinase CDK1 might control directly FOXA1 by phosphorylation and other kinases indirectly by means of regulating other proteins. Full article

(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)

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26 pages, 9965 KiB

Open AccessArticle

Ethinylestradiol and Levonorgestrel as Active Agents in Normal Skin, and Pathological Conditions Induced by UVB Exposure: In Vitro and In Ovo Assessments

by Dorina Coricovac, Claudia Farcas, Cristian Nica, Iulia Pinzaru, Sebastian Simu, Dana Stoian, Codruta Soica, Maria Proks, Stefana Avram, Dan Navolan, Catalin Dumitru, Ramona Amina Popovici and Cristina Adriana Dehelean

Int. J. Mol. Sci. 2018, 19(11), 3600; https://doi.org/10.3390/ijms19113600 - 14 Nov 2018

Cited by 21 | Viewed by 5601

Abstract

The link between melanoma development and the use of oral combined contraceptives is not fully elucidated, and the data concerning this issue are scarce and controversial. In the present study, we show that the components of oral contraceptives, ethinylestradiol (EE), levonorgestrel (LNG), and their combination (EE + LNG) ± UVB (ultraviolet B radiation) induced differential effects on healthy (human keratinocytes, fibroblasts, and primary epidermal melanocytes, and murine epidermis cells) and melanoma cells (human—A375 and murine—B164A5), as follows: (i) at low doses (1 µM), the hormones were devoid of significant toxicity on healthy cells, but in melanoma cells, they triggered cell death via apoptosis; (ii) higher doses (10 µM) were associated with cytotoxicity in all cells, the most affected being the melanoma cells; (iii) UVB irradiation proved to be toxic for all types of cells; (iv) UVB irradiation + hormonal stimulation led to a synergistic cytotoxicity in the case of human melanoma cells—A375 and improved viability rates of healthy and B164A5 cells. A weak irritant potential exerted by EE and EE + LNG (10 µM) was assessed by the means of a chick chorioallantoic membrane assay. Further studies are required to elucidate the hormones’ cell type-dependent antimelanoma effect and the role played by melanin in this context. Full article

(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)

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12 pages, 2812 KiB

Open AccessArticle

BRCA1 Interacting Protein COBRA1 Facilitates Adaptation to Castrate-Resistant Growth Conditions

by Huiyoung Yun, Roble Bedolla, Aaron Horning, Rong Li, Huai-Chin Chiang, Tim-H Huang, Robert Reddick, Aria F. Olumi, Rita Ghosh and Addanki P. Kumar

Int. J. Mol. Sci. 2018, 19(7), 2104; https://doi.org/10.3390/ijms19072104 - 20 Jul 2018

Cited by 5 | Viewed by 4222

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 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)

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21 pages, 3701 KiB

Open AccessArticle

by Matteo Capaia, Ilaria Granata, Mario Guarracino, Andrea Petretto, Elvira Inglese, Carlo Cattrini, Nicoletta Ferrari, Francesco Boccardo and Paola Barboro

Int. J. Mol. Sci. 2018, 19(7), 1920; https://doi.org/10.3390/ijms19071920 - 30 Jun 2018

Cited by 16 | Viewed by 4751

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 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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9 pages, 2759 KiB

Open AccessArticle

Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract

by Satoshi Inoue, Hiroki Ide, Kazutoshi Fujita, Taichi Mizushima, Guiyang Jiang, Takashi Kawahara, Seiji Yamaguchi, Hiroaki Fushimi, Norio Nonomura and Hiroshi Miyamoto

Int. J. Mol. Sci. 2018, 19(3), 777; https://doi.org/10.3390/ijms19030777 - 8 Mar 2018

Cited by 8 | Viewed by 3557

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 (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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15 pages, 6277 KiB

Open AccessArticle

Sex Hormone Receptors in Benign and Malignant Salivary Gland Tumors: Prognostic and Predictive Role

by Gabriella Aquino, Francesca Collina, Rocco Sabatino, Margherita Cerrone, Francesco Longo, Franco Ionna, Nunzia Simona Losito, Rossella De Cecio, Monica Cantile, Giuseppe Pannone and Gerardo Botti

Int. J. Mol. Sci. 2018, 19(2), 399; https://doi.org/10.3390/ijms19020399 - 30 Jan 2018

Cited by 11 | Viewed by 4529

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 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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Review

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16 pages, 2993 KiB

Open AccessReview

G-Protein Coupled Estrogen Receptor in Breast Cancer

by Li-Han Hsu, Nei-Min Chu, Yung-Feng Lin and Shu-Huei Kao

Int. J. Mol. Sci. 2019, 20(2), 306; https://doi.org/10.3390/ijms20020306 - 14 Jan 2019

Cited by 66 | Viewed by 8907

Abstract

The G-protein coupled estrogen receptor (GPER), an alternate estrogen receptor (ER) with a structure distinct from the two canonical ERs, being ERα, and ERβ, is expressed in 50% to 60% of breast cancer tissues and has been presumed to be associated with the development of tamoxifen resistance in ERα positive breast cancer. On the other hand, triple-negative breast cancer (TNBC) constitutes 15% to 20% of breast cancers and frequently displays a more aggressive behavior. GPER is prevalent and involved in TNBC and can be a therapeutic target. However, contradictory results exist regarding the function of GPER in breast cancer, proliferative or pro-apoptotic. A better understanding of the GPER, its role in breast cancer, and the interactions with the ER and epidermal growth factor receptor will be beneficial for the disease management and prevention in the future. Full article

(This article belongs to the Special Issue Sex Hormone Receptor Signals in Human Malignancies)

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