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Role of RAI2 Protein in the Progression of Prostate and Breast Cancer

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Role of RAI2 Protein in the Progression of Prostate and Breast Cancer Katharina Besler Role of RAI2 protein in the progression of prostate and breast cancer D I S S E R T A T I O N Dissertation With the aim of obtaining a doctoral degree (Dr. rer. nat.) at the Department of Biology Faculty of Mathematics, Informatics and Life Sciences University of Hamburg Submitted by KATHARINA BESLER Born in Kostanay, Kazakhstan Hamburg, May 2020 The present study was carried out between April 2016 and April 2020 at the University Medical Center Hamburg-Eppendorf in the Institute of Tumour Biology under the direction of Prof. Dr. Klaus Pantel and the supervision of Dr. Stefan Werner and Prof. Dr. Harriet Wikman-Kocher. 1. Reviewer : Prof. Dr. Christian Lohr 2. Reviewer : Prof. Dr. Wikman -Kocher Date of oral defense : September 11 th 2020 Abstract I Abstract The RAI2 gene was first identified as a novel metastasis suppressor gene in breast cancer patients with hormone-dependent disease. Moreover, low RAI2 expression was significantly associated with early occurring bone micro-metastasis and poor patients' outcome. Molecular characteriza- tion of the RAI2 protein in the ER-positive luminal breast cancer cell lines suggested that the RAI2 protein could act as a transcriptional co-regulator involved in differentiation of hormone-de- pendent breast cancer cells, and might play an active part in the transcriptional network of hor- monal response. In this study the role of RAI2 in prostate and breast cancer, both steroid hormone driven cancers, was evaluated focusing mainly on its impact on hormone response and progres- sion to a hormone therapy resistant disease. First, the prognostic relevance of RAI2 expression in prostate cancer was determined from pub- lished GEO datasets. To clarify whether there is a functional relationship between RAI2 and hor- mone receptor expression, knockdown or inhibition of either oestrogen (ER) or androgen recep- tors (AR) and RAI2 depletion were performed in hormone-dependent breast or prostate cancer cell lines. Furthermore, quantitative PCR analyses were performed to investigate the expression of AR-regulated genes in RAI2-depleted LNCaP prostate cancer cells. In addition, a possible mo- lecular interaction between RAI2, CtBP and the AR proteins was analysed using immunofluores- cence staining. To study the effect of the RAI2 protein on breast and prostate cancer cell line progression, both RAI2 knockout and RAI2 overexpression systems were generated. The effects of modified RAI2 expression on proliferation, cell response to pharmacological inhibition, an- chorage-independent growth and cell migration were also investigated. Also, growth and dissem- ination of LNCaP prostate cancer cells with RAI2-knockout was analysed in a xenograft model. Finally, to evaluate the clinical relevance of RAI2 expression in blood samples of advanced pros- tate patients, a method was established to measure RAI2 mRNA expression of circulating tumour cells. The feasibility of this method was tested within a small pilot study comprising 36 patients with metastatic prostate cancer. Results of this study showed, on the one hand, a decrease in ER and AR expression in all tested breast and prostate cancer cell lines as a result of RAI2 knockdown. On the other hand, the deple- tion of the respective HR increased the RAI2 protein expression in all tested cell lines of both tumour entities. This implies an interdependent regulation of the expression of these two proteins. Furthermore, pharmacological inhibition of HR led to significant changes in RAI2 expression, which in most cases correlated with the expression of the growth hormone receptor. Since RAI2 depletion causes elevated PSA gene expression in LNCaP cells and the RAI2 protein is colocalised Abstract II with CtBP factors in the nucleus, it is likely that the protein acts as transcriptional coregulator also in prostate cancer cells. With regard to proliferation and cell viability, the RAI2 knockout did lead to divergent results in the cell lines tested. Only in the LNCaP cells could a significant increase in proliferation be de- tected, which was also found increased in RAI2-KO cells even under inhibition of the AR. More- over, the RAI2 knockout was associated with an increased migration of LNCaP cells and an in- creased resistance to the anoikis. However, neither increased tumour growth nor increased dis- semination of LNCaP RAI2-KO cells could be detected in the xenograft mouse model. Finally, a method was successfully established that allows determination of gene expression of RAI2 , as well as other genes relevant for the progression of prostate cancer in CTCs. In the analysed blood sam- ples from patients with metastatic prostate cancer, RAI2 expression strongly correlated with the CTC status and the expression of AR, it’s constitutively active variant and the AR-regulated genes PSA and PSMA . Furthermore RAI2 expression was associated with increasing serum PSA levels, anemia and a tendency to worse overall survival. Taken together, the results of this study show a strong correlation and functional association be- tween the RAI2 protein and the steroid hormone receptors ER and AR in cell line models and patient material. Furthermore, a coregulatory function of the RAI2 protein is likely, mainly due to its interaction with the CtBP proteins, which act as coregulators of ER- and AR-mediated tran- scription. Despite the observed similarities between the tested breast and prostate cancer cell lines, proliferation and resistance to hormone therapy seems not only to depend on RAI2 but also on the cell-specific genetic aberrations of the individual cell line. Furthermore, a newly established liquid biopsy approach allows detection of the presence of CTC in the blood of patients with met- astatic prostate cancer based on the gene expression of RAI2 , AR , AR-V7 , PSA (KLK3) and PSMA (FOLH1) . However, the exact molecular function of the RAI2 protein requires clarification as well as whether detection of RAI2 gene expression could be exploited to enhance the treatment of metastatic prostate cancer. Zusammenfassung III Zusammenfassung Das RAI2-Gen wurde erstmals als ein mögliches Metastasierungssuppressor-Gen bei Brustkrebs- patientinnen mit hormonabhängiger Erkrankung identifiziert. Darüber hinaus korrelierte eine geringe RAI2-Expression mit früh auftretenden Micro-Knochenmetastasen und damit einherge- hendem verschlechtertem Krankheitsverlauf bei den betroffenen Patientinnen. Die molekulare Charakterisierung des RAI2-Proteins in den ER-positiven, luminalen Brustkrebszelllinien ließ zu- dem vermuten, dass das RAI2-Protein als transkriptioneller Co-Regulator bei der Differenzierung von hormonabhängigen Brustkrebszellen wirken und möglicherweise eine aktive Rolle im tran- skriptionellen Netzwerk der Hormonreaktion spielen könnte. In dieser Studie sollte die Bedeu- tung von RAI2 für die Progression des Brust- und Prostatakarzinoms weitergehend analysiert werden. Aufgrund des hormonabhängigen Wachstums beider Krebsarten wurde ein besonderer Fokus der Analysen auf den Einfluss des RAI2 Proteins auf die Hormonantwort, sowie die Ent- wicklung einer gegenüber Hormontherapie resistenten und Erkrankung gelegt. Um die prognostische Relevanz von RAI2 beim Fortschreiten des Prostatakarzinoms erstmalig zu untersuchen, wurde zunächst auf bereits publizierte GEO Datensätze zurückgegriffen. Um zu klä- ren, ob es einen funktionellen Zusammenhang zwischen der RAI2-Expression und der Expres- sion der Hormonrezeptoren gibt, wurden diese Proteine wechselseitig in Hormon-abhängigen Krebszelllinien depletiert. Des Weiteren wurden quantitative PCR Analysen durchgeführt, um die Expression von AR-regulierten Genen in RAI2-depletierten LNCaP Prostatakrebs Zelllinien zu untersuchen. Unter Anwendung einer Immunfluoreszenzfärbung, sollte zudem eine mögliche Interaktion zwischen dem RAI2, dem AR und den CtBP Proteinen untersucht werden. Um die Auswirkung des RAI2 Proteins auf die Progression von Brust- und Prostatakrebs-Zelllinien zu untersuchen wurden Zelllinien mit einer RAI2-Inaktivierung und mit konstitutiver RAI2-Über- expressions generiert. Die Auswirkungen dieser Modifikationen auf die Proliferation, das An- sprechen der Zellen auf pharmakologische Inhibition sowie das verankerungsunabhängige Wachstum und die Zell Migration wurden anschließend in den genetisch modifizierten Zellen untersucht. Darüber hinaus wurde das Wachstum und die Dissemination der modifizierten LNCaP Prostatkrebszellen in einem Xenograft Model, analysiert. Um die klinische Relevanz der RAI2-Expression bei fortgeschrittenen Prostatapatienten zu evaluieren, wurde außerdem eine Methode zur Messung der RAI2-Expression in zirkulierenden Tumorzellen etabliert und inner- halb einer kleinen Studie an 36 Patienten mit metastatischem Prostatakarzinom getestet. Untersuchungen dieser Arbeit zeigten, zum einen eine Verringerung der ER- und AR-Expression bei allen getesteten Brust- und Prostatakrebs Zelllinien infolge eines RAI2-Knockdowns. Ande- rerseits erhöhte die Depletion des jeweiligen HR die RAI2 Protein Expression in den Zelllinien Zusammenfassung IV beider Tumorentitäten, was eine voneinander abhängige Regulation der Expression beider Pro- teine impliziert. Des Weiteren führte die pharmakologische Inhibition der HR zu einer signifi- kanten Veränderung der RAI2-Expression, die in den meisten Fällen mit der Expression des wachstumstreibenden Hormonrezeptors korrelierte. Zusammen mit der erhöhten Expression des PSA Gens in vollständig RAI2-depletierten LNCaP Zellen und einer Interaktion der RAI2 und CtBP Proteine,
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