Aberrant TGF-β Signaling Drives Castration-Resistant Prostate Cancer in a Male Mouse Model of Prostate Tumorigenesis.

Abstract

The androgen receptor (AR) plays a critical role as a driver of castration-resistant prostate cancer (CRPC). Our previous studies demonstrated that disruption of transforming growth factor-β (TGF-β) signaling via introduction of dominant-negative transforming growth factor-β type II receptor (DNTGFβRII) in the prostate epithelium of transgenic adenocarcinoma of the prostate mice accelerated tumor. This study investigated the consequences of disrupted TGF-β signaling on prostate tumor growth under conditions of castration-induced androgen deprivation in the preclinical model of DNTGFβRII. Our results indicate that in response to androgen deprivation therapy (ADT) the proliferative index in prostate tumors from DNTGFβRII mice was higher compared with prostate tumors from TGFβRII wild-type (WT) mice, whereas there was a reduced incidence of apoptosis in tumors from DNTGFβRII. Protein and gene expression profiling revealed that tumors from DNTGFβRII mice exhibit a strong nuclear AR localization among the prostate tumor epithelial cells and increased AR messenger RNA after ADT. In contrast, TGFβRII WT mice exhibited a marked loss in nuclear AR in prostate tumor acini (20 weeks), followed by a downregulation of AR and transmembrane protease serine 2 messenger RNA. There was a significant increase in nuclear AR and activity in prostate tumors from castrate DNTGFβRII compared with TGFβRII WT mice. Consequential to aberrant TGF-β signaling, ADT enhanced expression and nuclear localization of Smad4 and β-catenin. Our findings support that under castrate conditions, aberrant TGF-β signaling leads to AR activation and β-catenin nuclear localization, an adaptation mechanism contributing to emergence of CRPC. The work defines a potentially significant new targeting platform for overcoming therapeutic resistance in CRPC.

• Authors: Hong Pu, Diane E Begemann, Natasha Kyprianou
• Journal: Endocrinology (Endocrinology) Vol. 158 Issue 6 Pg. 1612-1622 (06 01 2017) ISSN: 1945-7170 [Electronic] United States
• PMID: 28324007 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Endocrine Society.

Chemical References

• Receptors, Transforming Growth Factor beta
• Receptors, Tumor Necrosis Factor, Member 25
• Tnfrsf25 protein, mouse
• Transforming Growth Factor beta
• beta Catenin
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II

Topics

• Animals
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Disease Models, Animal
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Prostatic Neoplasms, Castration-Resistant (genetics, metabolism, pathology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Receptors, Tumor Necrosis Factor, Member 25 (genetics)
• Signal Transduction (drug effects)
• Transforming Growth Factor beta (metabolism, pharmacology)
• beta Catenin (metabolism)