The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis

Preclinical and/or clinical evidence has indicated a potential role of steroid hormone-mediated signaling pathways in the development of various neoplastic diseases, while precise mechanisms for the functions of specific receptors remain poorly understood. Specifically, in urothelial cancer where sex-related differences particularly in its incidence are noted, activation of sex hormone receptors, such as androgen receptor and estrogen receptor-β, has been associated with the induction of tumor development. More recently, glucocorticoid receptor has been implied to function as a suppressor of urothelial tumorigenesis. This article summarizes and discusses available data suggesting that steroid hormone receptors, including androgen receptor, estrogen receptor-α, estrogen receptor-β, glucocorticoid receptor, progesterone receptor and vitamin D receptor, as well as their related signals, contribute to modulating urothelial tumorigenesis.

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Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer

10.1101/199448 ◽

2017 ◽

Cited By ~ 1

Author(s):

Jeffery M. Vahrenkamp ◽

Chieh-Hsiang Yang ◽

Adriana C. Rodriguez ◽

Aliyah Almomen ◽

Kristofer C. Berrett ◽

...

Keyword(s):

Estrogen Receptor ◽

Endometrial Cancer ◽

Glucocorticoid Receptor ◽

Hormone Receptors ◽

Steroid Hormone ◽

Estrogen Receptor Α ◽

Steroid Hormone Receptors ◽

Uterine Growth ◽

Opposing Effects

SummarySteroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is significantly altered by estradiol with GR recruited to ER bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol, but with novel regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer.

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Co-expression of steroid hormone receptors (estrogen receptor α and/or progesterone receptors) and Her2/neu (c-erbB-2) in breast cancer: Clinical outcome following tamoxifen-based adjuvant therapy

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2005.07.002 ◽

2006 ◽

Vol 98 (1) ◽

pp. 36-40 ◽

Cited By ~ 13

Author(s):

Francisco E. Gago ◽

Mariel A. Fanelli ◽

Daniel R. Ciocca

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Adjuvant Therapy ◽

Clinical Outcome ◽

Hormone Receptors ◽

Steroid Hormone ◽

Progesterone Receptors ◽

Estrogen Receptor Α ◽

Steroid Hormone Receptors

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Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy

Cells ◽

10.3390/cells10051169 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1169

Author(s):

Hiroki Ide ◽

Hiroshi Miyamoto

Keyword(s):

Bladder Cancer ◽

Estrogen Receptor ◽

Androgen Receptor ◽

Surgical Therapy ◽

Urothelial Cancer ◽

Hormone Receptors ◽

Estrogen Receptor Α ◽

Vital Role ◽

Sex Hormone ◽

Sex Steroid Hormone

There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.

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877 ROLE OF STEROID HORMONE RECEPTORS ON FORMATION AND PROGRESSION OF BLADDER CARCINOMA

The Journal of Urology ◽

10.1016/j.juro.2011.02.701 ◽

2011 ◽

Vol 185 (4S) ◽

Author(s):

Gholamreza Pourmand ◽

Sepehr Salem ◽

Abdolrasoul Mehrsai ◽

Farid Kosari

Keyword(s):

Bladder Carcinoma ◽

Hormone Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors

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Comparative analysis of the influence of the high-mobility group box 1 protein on DNA binding and transcriptional activation by the androgen, glucocorticoid, progesterone and mineralocorticoid receptors

Biochemical Journal ◽

10.1042/bj3610097 ◽

2001 ◽

Vol 361 (1) ◽

pp. 97-103 ◽

Cited By ~ 32

Author(s):

Guy VERRIJDT ◽

Annemie HAELENS ◽

Erik SCHOENMAKERS ◽

Wilfried ROMBAUTS ◽

Frank CLAESSENS

Keyword(s):

Androgen Receptor ◽

Comparative Analysis ◽

Dna Binding ◽

Mineralocorticoid Receptor ◽

Hormone Receptors ◽

Steroid Hormone ◽

High Mobility ◽

Steroid Hormone Receptors ◽

High Mobility Group ◽

Mineralocorticoid Receptors

We performed a comparative analysis of the effect of high-mobility group box protein 1 (HMGB1) on DNA binding by the DNA-binding domains (DBDs) of the androgen, glucocorticoid, progesterone and mineralocorticoid receptors. The affinity of the DBDs of the different receptors for the tyrosine aminotransferase glucocorticoid response element, a classical high-affinity binding element, was augmented up to 7-fold by HMGB1. We found no major differences in the effects of HMGB1 on DNA binding between the different steroid hormone receptors. In transient transfection assays, however, HMGB1 significantly enhances the activity of the glucocorticoid and progesterone receptors but not the androgen or mineralocorticoid receptor. We also investigated the effect of HMGB1 on the binding of the androgen receptor DBD to a subclass of directly repeated response elements that is recognized exclusively by the androgen receptor and not by the glucocorticoid, progesterone or mineralocorticoid receptor. Surprisingly, a deletion of 26 amino acid residues from the C-terminal extension of the androgen receptor DBD does not influence DNA binding but destroys its sensitivity to HMGB1. Deletion of the corresponding fragment in the DBDs of the glucocorticoid, progesterone and mineralocorticoid receptor destroyed their DNA binding. This 26-residue fragment is therefore essential for the influence of HMGB1 on DNA recognition by all steroid hormone receptors that were tested. However, it is dispensable for DNA binding by the androgen receptor.

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Molecular cloning of androgen receptor and gene expression of sex steroid hormone receptors in the brain of newborn Chinese alligator (Alligator sinensis)

Gene ◽

10.1016/j.gene.2018.06.033 ◽

2018 ◽

Vol 674 ◽

pp. 178-187 ◽

Cited By ~ 1

Author(s):

Ruidong Zhang ◽

Ying Zhang ◽

Mengjuan Wu ◽

Peng Yan ◽

Ali Izaz ◽

...

Keyword(s):

Gene Expression ◽

Androgen Receptor ◽

Hormone Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Sex Steroid ◽

Sex Steroid Hormone ◽

Chinese Alligator ◽

Alligator Sinensis ◽

The Brain

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Functional interaction of hybrid response elements with wild-type and mutant steroid hormone receptors.

Molecular and Cellular Biology ◽

10.1128/mcb.11.6.3247 ◽

1991 ◽

Vol 11 (6) ◽

pp. 3247-3258 ◽

Cited By ~ 34

Author(s):

M Truss ◽

G Chalepakis ◽

E P Slater ◽

S Mader ◽

M Beato

Keyword(s):

Glucocorticoid Receptor ◽

Hormone Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Single Amino Acid ◽

Wild Type ◽

Binding Domains ◽

Responsive Element

Steroid hormone receptors can be divided into two subfamilies according to the structure of their DNA binding domains and the nucleotide sequences which they recognize. The glucocorticoid receptor and the progesterone receptor (PR) recognize an imperfect palindrome (glucocorticoid responsive element/progesterone responsive element [GRE/PRE]) with the conserved half-sequence TGTYCY, whereas the estrogen receptor (ER) recognizes a palindrome (estrogen responsive element) with the half-sequence TGACC. A series of symmetric and asymmetric variants of these hormone responsive elements (HREs) have been tested for receptor binding and for the ability to mediate induction in vivo. High-resolution analysis demonstrates that the overall number and distribution of contacts with the N-7 position of guanines and with the phosphate backbone of various HREs are quite similar for PR and ER. However, PR and glucocorticoid receptor, but not ER, are able to contact the 5'-methyl group of thymines found in position 3 of HREs, as shown by potassium permanganate interference. The ER mutant HE84, which contains a single amino acid exchange, Glu-203 to Gly, in the knuckle of ER, creates a promiscuous ER that is able to bind to GRE/PREs by contacting this thymine. Elements with the sequence GGTCAcagTGTYCT that represent hybrids between an estrogen response element and a GRE/PRE respond to estrogens, glucocorticoids, and progestins in vivo and bind all three wild-type receptors in vitro. These hybrid HREs could serve to confer promiscuous gene regulation.

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