The mouse as a model to investigate sex steroid metabolism in the normal and pathological prostate

McNamara, Keely May; Handelsman, David J.; Simanainen, Ulla

doi:10.1016/j.jsbmb.2011.10.009

Cited by 6 publications

(4 citation statements)

References 228 publications

(386 reference statements)

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“…Surprisingly, the fourth most affected signaling network by Atbf1 deletion was the estrogen-progesterone signaling network ( Figure 5 D). The presence of estrogen and progesterone receptors in prostate cancer has been documented [84] , and so has the role of estrogen in the development and progression of prostate cancer [85] , [86] . For example, androgen-responsive LNCaP prostate cancer cells are stimulated by estradiol for growth via estrogen receptors while the androgen-insensitive PC-3 prostate cancer cell proliferation is inhibited by estrogen [85] .…”

Section: Discussionmentioning

confidence: 99%

“…The role of estrogen and progesterone in prostate cancer is better documented in mouse models [86] . Further supporting the effect of Atbf1 deletion on estrogen signaling, our previous studies demonstrated that in breast cancer cells estrogen signaling upregulates ATBF1 transcription but causes ATBF1 protein degradation [89] , [90] , while ATBF1 inhibits ERα function by selectively competing with one of its coactivators for the binding to ERα [91] .…”

Section: Discussionmentioning

confidence: 99%

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Deletion of Atbf1/Zfhx3 In Mouse Prostate Causes Neoplastic Lesions, Likely by Attenuation of Membrane and Secretory Proteins and Multiple Signaling Pathways

Sun¹,

Fu²,

Li³

et al. 2014

Neoplasia

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The ATBF1/ZFHX3 gene at 16q22 is the second most frequently mutated gene in human prostate cancer and has reduced expression or mislocalization in several types of human tumors. Nonetheless, the hypothesis that ATBF1 has a tumor suppressor function in prostate cancer has not been tested. In this study, we examined the role of ATBF1 in prostatic carcinogenesis by specifically deleting Atbf1 in mouse prostatic epithelial cells. We also examined the effect of Atbf1 deletion on gene expression and signaling pathways in mouse prostates. Histopathologic analyses showed that Atbf1 deficiency caused hyperplasia and mouse prostatic intraepithelial neoplasia (mPIN) primarily in the dorsal prostate but also in other lobes. Hemizygous deletion of Atbf1 also increased the development of hyperplasia and mPIN, indicating a haploinsufficiency of Atbf1. The mPIN lesions expressed luminal cell markers and harbored molecular changes similar to those in human PIN and prostate cancer, including weaker expression of basal cell marker cytokeratin 5 (Ck5), cell adhesion protein E-cadherin, and the smooth muscle layer marker Sma; elevated expression of the oncoproteins phospho-Erk1/2, phospho-Akt and Muc1; and aberrant protein glycosylation. Gene expression profiling revealed a large number of genes that were dysregulated by Atbf1 deletion, particularly those that encode for secretory and cell membrane proteins. The four signaling networks that were most affected by Atbf1 deletion included those centered on Erk1/2 and IGF1, Akt and FSH, NF-κB and progesterone and β-estradiol. These findings provide in vivo evidence that ATBF1 is a tumor suppressor in the prostate, suggest that loss of Atbf1 contributes to tumorigenesis by dysregulating membrane and secretory proteins and multiple signaling pathways, and provide a new animal model for prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Deletion of Atbf1/Zfhx3 In Mouse Prostate Causes Neoplastic Lesions, Likely by Attenuation of Membrane and Secretory Proteins and Multiple Signaling Pathways

Sun¹,

Fu²,

Li³

et al. 2014

Neoplasia

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“…This review summarizes in vitro cell models currently available to study AR signaling with particular focus on their use in addressing key questions relating to the development and progression of PCa. It is beyond the scope of the current review to discuss in vivo models, which have been reviewed recently elsewhere (Hensley & Kyprianou 2012, McNamara et al 2012, Toivanen et al 2012.…”

Section: Introductionmentioning

confidence: 99%

In vitro model systems to study androgen receptor signaling in prostate cancer

Sampson

Neuwirt

Puhr

et al. 2013

Endocrine-Related Cancer

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Prostate cancer (PCa) is one of the most common causes of male cancer-related death in Western nations. The cellular response to androgens is mediated via the androgen receptor (AR), a ligand-inducible transcription factor whose dysregulation plays a key role during PCa development and progression following androgen deprivation therapy, the current mainstay systemic treatment for advanced PCa. Thus, a better understanding of AR signaling and new strategies to abrogate AR activity are essential for improved therapeutic intervention. Consequently, a large number of experimental cell culture models have been established to facilitate in vitro investigations into the role of AR signaling in PCa development and progression. These different model systems mimic distinct stages of this heterogeneous disease and exhibit differences with respect to AR expression/status and androgen responsiveness. Technological advances have facilitated the development of in vitro systems that more closely reflect the physiological setting, for example via the use of three-dimensional coculture to study the interaction of prostate epithelial cells with the stroma, endothelium, immune system and tissue matrix environment. This review provides an overview of the most commonly used in vitro cell models currently available to study AR signaling with particular focus on their use in addressing key questions relating to the development and progression of PCa. It is hoped that the continued development of in vitro models will provide more biologically relevant platforms for mechanistic studies, drug discovery and design ensuring a more rapid transfer of knowledge from the laboratory to the clinic.

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“…The simultaneous quantification of DHT and its metabolites from the serum of HEXIM1 knockout mice should help us to determine the role of HEXIM1 in androgen metabolism. The enzymatic pathways present in mouse and human prostate share some similarities and some differences, and the enzymes regulated by HEXIM1 are similar in the mouse and human prostate [37]. The method developed describes the simultaneous quantitation of DHT and its metabolites and is expected to contribute to the advancement of prostate cancer research.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous determination of dihydrotestosterone and its metabolites in mouse sera by LC-MS/MS with chemical derivatization

Gorityala

Yang

Montano

et al. 2018

Journal of Chromatography B

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Androgens play a vital role in prostate cancer development, and their elimination and blockade are essential in the disease management. DHT is the key ligand for androgen receptor (AR) in the prostate. It is locally synthesized from testosterone. In the prostate, DHT is predominantly metabolized to α-diol and β-diol. Recent studies indicate that impaired DHT catabolism is associated with prostate cancer, signifying the necessity of a sensitive quantitative method for the determination of DHT and its metabolites. In this work, an LC-MS/MS method for the simultaneous quantification of DHT and its metabolites was developed and validated. Steroid-free sera were prepared and used for the preparation of sera calibrators and quality controls (QCs). DHT and its metabolites along with their respective stable heavy isotope labeled analytes representing internal standards were first extracted with methyl tertiary-butyl ether (MTBE) and derivatized with picolinic acid (PA). The derivatized analytes were then extracted again with MTBE, dried under nitrogen and reconstituted in the mobile phase (80% methanol and 0.2% formic acid in water). Baseline chromatographic separation of the derivatized analytes was achieved isocratically on XTerra C18 column (2.1 × 100 mm) using the mobile phase at a flow rate of 0.25 mL/min. Quantitation was performed using multiple-reaction-monitoring mode with positive electrospray ionization. The method has calibration ranges from 0.0500 ng/mL to 50.0 ng/mL for DHT and its two metabolites with acceptable assay precision, accuracy, recovery, and matrix factor. It was applied to the determination of DHT and its metabolites in an animal study.

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The mouse as a model to investigate sex steroid metabolism in the normal and pathological prostate

Cited by 6 publications

References 228 publications

Deletion of Atbf1/Zfhx3 In Mouse Prostate Causes Neoplastic Lesions, Likely by Attenuation of Membrane and Secretory Proteins and Multiple Signaling Pathways

Deletion of Atbf1/Zfhx3 In Mouse Prostate Causes Neoplastic Lesions, Likely by Attenuation of Membrane and Secretory Proteins and Multiple Signaling Pathways

In vitro model systems to study androgen receptor signaling in prostate cancer

Simultaneous determination of dihydrotestosterone and its metabolites in mouse sera by LC-MS/MS with chemical derivatization

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