Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1

Nicholas, Taylor R.; Metcalf, Stephanie; Greulich, Benjamin M; Hollenhorst, Peter C.

doi:10.1093/narcan/zcab033

Cited by 6 publications

(2 citation statements)

References 65 publications

(79 reference statements)

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“…A similar process could occur in the DSRCT cell of origin to initiate EWSR1::WT1 translocation. This hypothesis is bolstered by recent findings from Nicholas et al showing that AR binds to introns 5 and 8 of EWSR1 in prostate cancer and further, that R1881 treatment can increase chromosomal breakage at this site in an R-loop dependent manner 31 . In fact, intron 7 of EWSR1, located between the two AR binding sites, is the most common breakpoint location in DSRCT.…”

Section: Discussionmentioning

confidence: 95%

Enzalutamide Induces Cytotoxicity in Desmoplastic Small Round Cell Tumor Independent of the Androgen Receptor

Magrath,

Goldberg,

Truong

et al. 2023

Preprint

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Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growthin vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.

show abstract

Section: Discussionmentioning

confidence: 95%

Enzalutamide Induces Cytotoxicity in Desmoplastic Small Round Cell Tumor Independent of the Androgen Receptor

Magrath,

Goldberg,

Truong

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…It has been reported that highly active transcription of the EWSR1 locus could induce the formation of R-loops that in turn favor double-strand breaks. Nicholas et al [29], using prostate cancer cell lines, reported that androgen receptors promoted breakpoint generation in an intronic polyadenylation site of EWSR1 near the Ewing sarcoma breakpoint hotspot, which was dependent on the formation of R-loops. Indeed, persistent R-loops are a direct cause of chromosomal rearrangements [30].…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms

Salguero-Aranda,

Di Blasi,

Galán

et al. 2024

IJMS

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Recurrent gene fusions (GFs) in translocated sarcomas are recognized as major oncogenic drivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a ‘promiscuous’ gene that can fuse with many different partner genes, defining different entities among a broad range of mesenchymal neoplasms. Molecular testing of EWSR1 translocation traditionally relies on FISH assays with break-apart probes, which are unable to identify the fusion partner. Therefore, other ancillary molecular diagnostic modalities are being increasingly adopted for accurate classification of these neoplasms. Herein, we report three cases with rare GFs involving EWSR1 in undifferentiated mesenchymal neoplasms with uncertain differential diagnoses, using targeted RNA-seq and confirming with RT-PCR and Sanger sequencing. Two GFs involved hormone nuclear receptors as 3′ partners, NR4A2 and RORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3′ partner in extraskeletal myxoid chondrosarcoma. The third GF, EWSR1::BEND2, has previously been reported in a subtype of astroblastoma and other rare entities, including a single case of a soft-tissue tumor that we discuss in this work. In conclusion, our findings indicate that the catalogue of mesenchymal neoplasm-bearing EWSR1 fusions continues to grow, underscoring the value of using molecular ancillary techniques with higher diagnostic abilities in the routine clinical setting.

show abstract

Enzalutamide induces cytotoxicity in desmoplastic small round cell tumor independent of the androgen receptor

Magrath,

Goldberg,

Truong

et al. 2024

Commun Biol

View full text Add to dashboard Cite

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growth in vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.

show abstract

Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1

Cited by 6 publications

References 65 publications

Enzalutamide Induces Cytotoxicity in Desmoplastic Small Round Cell Tumor Independent of the Androgen Receptor

Enzalutamide Induces Cytotoxicity in Desmoplastic Small Round Cell Tumor Independent of the Androgen Receptor

Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms

Enzalutamide induces cytotoxicity in desmoplastic small round cell tumor independent of the androgen receptor

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