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Molecular features of prostate cancer bone metastases harboring androgen receptor gene amplification
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.ORCID iD: 0000-0001-7175-1336
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The relation between AR amplification and other mechanisms behind castration-resistance in prostate cancer, such as increased expression of AR splice variants and steroid-converting enzymes in CRPC metastases, has been poorly examined. Specific aims of this study were therefore to examine AR amplification in hormone-naïve and castration-resistant prostate cancer (CRPC) bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying molecular targets for treatment of CRPC bone metastases. AR amplification was assessed by fluorescence in situ hybridization and verified in 16 (53 %) of the CRPC bone metastases (n=30), and in none of the untreated bone metastases (n=10). AR amplification was associated with increased expression of AR and its constitutively active AR-V7 splice variant as well as with co-amplification of genes in the AR proximity at Xq12, such as of YIPF6. Furthermore, gene expression pattern pointed at decreased osteoclast activity, and consequently decreased bone resorption and increased bone mineral density in AR amplified metastases. In conclusion, our results indicated a sclerotic phenotype in CRPC bone metastases with AR amplification that may be of both biological and clinical relevance. This is a novel hypothesis that requires to be thoroughly examined.

National Category
Basic Medicine Cancer and Oncology
URN: urn:nbn:se:umu:diva-83841OAI: diva2:677745
Available from: 2013-12-10 Created: 2013-12-10 Last updated: 2016-08-22Bibliographically approved
In thesis
1. Mechanisms behind growth of castration-resistant prostate cancer bone metastases
Open this publication in new window or tab >>Mechanisms behind growth of castration-resistant prostate cancer bone metastases
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: The first-line treatment for patients with advanced prostate cancer (PC) is androgen deprivation therapy. This therapy is initially effective, but after some time tumors relapse, predominantly within the bone, and are then termed castration-resistant prostate cancer (CRPC). The majority of CRPC tumors show androgen receptor (AR) activity despite castrate levels of circulating testosterone. AR activity could be caused by several mechanisms including; intratumoral androgen synthesis, AR amplification, AR mutations and expression of AR splice variants. The mechanisms controlling CRPC growth in the clinically most relevant metastatic site, the bone, are not fully identified. The purpose of this thesis was therefore to explore AR expression and possible mechanisms behind CRPC growth in PC bone metastases in order to find mechanisms that could be targeted for treatment and/or predict response to certain therapies.

Materials and Methods: We have examined hormone-naïve and CRPC bone metastases samples obtained from patients at metastasis surgery, non-malignant and malignant prostate samples obtained from patients at radical prostatectomy, and PC cell lines cultured in vitro. Analysis has been performed using RT-PCR, whole-genome expression arrays, immunohistochemistry, western blotting, FISH, copy number assays and gene ontology analysis. Functional studies have been made by protein overexpression and knock-down in PC cells in vitro and effects studied by evaluation of cell viability, migration, and invasion.

Results: We found that high nuclear AR immunostaining (presumed to reflect high AR activity) in bone metastases from CRPC patients was associated with a particularly poor prognosis, while no difference in AR staining was observed between hormone-naïve and CRPC metastases. Further, expression of AR splice variants (AR-V7, AR-V567es) was associated with a high nuclear AR immunostaining score and shown to be increased in CRPC compared to hormone-naïve bone metastases. High levels (levels in the upper quartile) of AR splice variants in CRPC bone metastases was related to disturbed cell cycle regulation and short patients survival. No differences in steroidogenic enzyme levels were detected between CRPC and hormone-naïve bone metastases. Higher levels of enzymes involved in late steps of androgen synthesis (adrenal gland steroid conversion) were observed in bone metastases than in non-malignant and/or malignant prostate tissue, while the enzyme levels in earlier steps (de novo steroidogenesis) were lower in bone metastases. A subgroup of metastases expressed very high levels of AKR1C3, indicating that this group may have an induced capacity of converting adrenal-gland derived steroids into more potent androgens. This was not associated to CRPC but merely with the advanced stage of metastasis. High protein levels of AR splice variants were found in bone metastases with low AKR1C3 levels, while metastases with high AKR1C3 levels primarily contained low AR variant levels. Furthermore, about half of the CRPC bone metastases showed androgen receptor gene amplification which was associated with co-amplification of YIPF6, and a gene expression pattern that pointed at decreased osteoclast activity, and consequently decreased bone resorption.

Conclusions: The majority of CRPC bone metastases show high nuclear AR immunostaining that seems to be associated with a particularly unfavorable outcome after metastasis surgery. Subgroups of CRPC bone metastases could be identified according to presence of AR amplification and expression levels of AKR1C3 or AR splice variants, which might have clinical relevance for treatment of PC patients.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2013. 43 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1620
Prostate cancer, castration-resistance, bone metastases, androgen receptor, intratumoral steroidogenesis, androgen receptor splice variants, androgen receptor amplification
National Category
Cancer and Oncology Other Basic Medicine
Research subject
urn:nbn:se:umu:diva-83956 (URN)978-91-7459-775-2 (ISBN)
Public defence
2014-01-10, Sal B, 9tr, By 1D Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 09:00 (English)

Författaren är även publicerad med efternamnet Hörnberg.

Available from: 2013-12-18 Created: 2013-12-11 Last updated: 2014-01-15Bibliographically approved

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