Beyond Prostate Cancer: An Androgen Receptor Splice Variant Expression in Multiple Malignancies, Non-Cancer Pathologies, and Development.

Multiple studies have demonstrated the importance of androgen receptor (AR) splice variants (SVs) in the progression of prostate cancer to the castration-resistant phenotype and their utility as a diagnostic. However, studies on AR expression in non-prostatic malignancies uncovered that AR-SVs are expressed in glioblastoma, breast, salivary, bladder, kidney, and liver cancers, where they have diverse roles in tumorigenesis. AR-SVs also have roles in non-cancer pathologies. In granulosa cells from women with polycystic ovarian syndrome, unique AR-SVs lead to an increase in androgen production. In patients with nonobstructive azoospermia, testicular Sertoli cells exhibit differential expression of AR-SVs, which is associated with impaired spermatogenesis. Moreover, AR-SVs have been identified in normal cells, including blood mononuclear cells, neuronal lipid rafts, and the placenta. The detection and characterization of AR-SVs in mammalian and non-mammalian species argue that AR-SV expression is evolutionarily conserved and that AR-SV-dependent signaling is a fundamental regulatory feature in multiple cellular contexts. These discoveries argue that alternative splicing of the AR transcript is a commonly used mechanism that leads to an expansion in the repertoire of signaling molecules needed in certain tissues. Various malignancies appropriate this mechanism of alternative AR splicing to acquire a proliferative and survival advantage.

Androgen receptor-dependent regulation of metabolism in high grade bladder cancer cells.

The observed sex disparity in bladder cancer (BlCa) argues that androgen receptor (AR) signaling has a role in these malignancies. BlCas express full-length AR (FL-AR), constitutively active AR splice variants, including AR-v19, or both, and their depletion limits BlCa viability. However, the mechanistic basis of AR-dependence is unknown. Here, we depleted FL-AR, AR-v19, or all AR forms (T-AR), and performed RNA-seq studies to uncover that different AR forms govern distinct but partially overlapping transcriptional programs. Overlapping alterations include a decrease in mTOR and an increase of hypoxia regulated transcripts accompanied by a decline in oxygen consumption rate (OCR). Queries of BlCa databases revealed a significant negative correlation between AR expression and multiple hypoxia-associated transcripts arguing that this regulatory mechanism is a feature of high-grade malignancies. Our analysis of a 1600-compound library identified niclosamide as a strong ATPase inhibitor that reduces OCR in BlCa cells, decreased cell viability and induced apoptosis in a dose and time dependent manner. These results suggest that BlCa cells hijack AR signaling to enhance metabolic activity, promoting cell proliferation and survival; hence targeting this AR downstream vulnerability presents an attractive strategy to limit BlCa.

Steroid regulation of early postnatal development in the corpus epididymidis of pigs.

Development of the epididymis including blood-epididymal barrier formation is not required until sperm reach the epididymis peripuberally. Regulation of this development in the early postnatal period is largely unknown. The current objectives were to evaluate potential roles of endogenous estrogen and androgen signaling during early development of the corpus epididymidis and to determine the timing of formation of the blood-epididymal barrier in the pig. Effects of endogenous steroids were evaluated using littermates treated with vehicle, an aromatase inhibitor (letrozole) to reduce endogenous estrogens, an estrogen receptor antagonist (fulvestrant) or an androgen receptor antagonist (flutamide). Phosphorylated histone 3 immunohistochemistry was used to identify proliferating epithelial cells. Lanthanum nitrate and electron microscopy were used to analyze formation of the blood barrier in the corpus epididymidis. Reducing endogenous estrogens increased the number of proliferating corpus epithelial cells at 6 and 6.5 weeks of age compared with vehicle-treated boars (P<0.01 and P<0.001 respectively). Blocking androgen receptors did not alter proliferation rate at 6.5 weeks of age. Although barrier formation was similar between 6 and 6.5 weeks of age in vehicle-treated animals, intercellular barriers increased in letrozole-treated littermates at 6.5 weeks of age. Fulvestrant treatment, which should mimic aromatase inhibition for regulation through ESR1 and ESR2 signaling but potentially stimulate endogenous estrogen signaling through the G protein-coupled estrogen receptor (GPER), had the opposite effect on aromatase inhibition. These responses in conjunction with the presence of GPER in the corpus epididymidis suggest early corpus epididymal development is regulated partially by GPER.