Universität zu Köln

Tolkach, Yuri, Kremer, Anika, Lotz, Gabor ORCID: 0000-0002-6921-8978, Schmid, Matthias, Mayr, Thomas ORCID: 0000-0002-2900-1782, Foerster, Sarah, Garbe, Stephan, Hosni, Sana ORCID: 0000-0002-2236-3836, Cronauer, Marcus, V, Kocsmar, Ildiko, Kocsmar, Eva ORCID: 0000-0003-3061-1323, Riesz, Peter, Alajati, Abdullah, Ritter, Manuel ORCID: 0000-0001-8667-2067, Ellinger, Joerg, Ohlmann, Carsten-Henning and Kristiansen, Glen (2022). Androgen Receptor Splice Variants Contribute to the Upregulation of DNA Repair in Prostate Cancer. Cancers, 14 (18). BASEL: MDPI. ISSN 2072-6694

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Abstract

Simple Summary Ligand-independent androgen receptor splice variants emerge during androgen deprivation therapy and are suspected to render prostate carcinomas castration-resistant. In a retrospective analysis of a large cohort of primary and advanced prostate tumors, we observed increased expression of androgen receptor splice variants in therapy refractory tumors. Our hypothesis was that AR splice variants exert their tumor-promoting activity by modulating the intrinsic DNA repair machinery. In the sequence from primary over advanced tumors under androgen-deprivation therapy to castration resistance, AR splice variant expression increases and is linked to increased expression of DNA repair genes. This effect of AR splice variants appeared independent of their known impact on tumor cell proliferation. These clinical findings were validated in an androgen-sensitive prostate cancer cell line that mimics a castration-resistant phenotype by overexpression of AR-V7. Modulated DNA repair gene expression in the presence of AR splice variants is linked to increased DNA repair activity, pointing at a novel therapeutic approach for castration-resistant prostate cancer. Background: Canonical androgen receptor (AR) signaling regulates a network of DNA repair genes in prostate cancer (PCA). Experimental and clinical evidence indicates that androgen deprivation not only suppresses DNA repair activity but is often synthetically lethal in combination with PARP inhibition. The present study aimed to elucidate the impact of AR splice variants (AR-Vs), occurring in advanced or late-stage PCA, on DNA repair machinery. Methods: Two hundred and seventy-three tissue samples were analyzed, including primary hormone-naive PCA, primary metastases, hormone-sensitive PCA on androgen deprivation therapy (ADT) and castration refractory PCA (CRPC group). The transcript levels of the target genes were profiled using the nCounter platform. Experimental support for the findings was gained in AR/AR-V7-expressing LNCaP cells subjected to ionizing radiation. Results: AR-Vs were present in half of hormone-sensitive PCAs on androgen deprivation therapy (ADT) and two-thirds of CRPC samples. The presence of AR-Vs is highly correlated with increased activity in the AR pathway and DNA repair gene expression. In AR-V-expressing CRPC, the DNA repair score increased by 2.5-fold as compared to AR-V-negative samples. Enhanced DNA repair and the deregulation of DNA repair genes by AR-V7 supported the clinical data in a cell line model. Conclusions: The expression of AR splice variants such as AR-V7 in PCA patients following ADT might be a reason for reduced or absent therapy effects in patients on additional PARP inhibition due to the modulation of DNA repair gene expression. Consequently, AR-Vs should be further studied as predictive biomarkers for therapy response in this setting.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Tolkach, Yuri UNSPECIFIED UNSPECIFIED UNSPECIFIED Kremer, Anika UNSPECIFIED UNSPECIFIED UNSPECIFIED Lotz, Gabor UNSPECIFIED orcid.org/0000-0002-6921-8978 UNSPECIFIED Schmid, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayr, Thomas UNSPECIFIED orcid.org/0000-0002-2900-1782 UNSPECIFIED Foerster, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Garbe, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hosni, Sana UNSPECIFIED orcid.org/0000-0002-2236-3836 UNSPECIFIED Cronauer, Marcus, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Kocsmar, Ildiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Kocsmar, Eva UNSPECIFIED orcid.org/0000-0003-3061-1323 UNSPECIFIED Riesz, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Alajati, Abdullah UNSPECIFIED UNSPECIFIED UNSPECIFIED Ritter, Manuel UNSPECIFIED orcid.org/0000-0001-8667-2067 UNSPECIFIED Ellinger, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Ohlmann, Carsten-Henning UNSPECIFIED UNSPECIFIED UNSPECIFIED Kristiansen, Glen UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-677215
DOI:	10.3390/cancers14184441
Journal or Publication Title:	Cancers
Volume:	14
Number:	18
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RESISTANCE; PARP-1; GROWTH; ROLES Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67721