Dissertation
Heterogeneity in androgen receptor and Interleukin-1 beta expression by prostate cancer cells in skeletal metastases
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2019
DOI:
https://doi.org/10.17918/fbxb-jm23
Abstract
Castration resistant prostate cancer (CRPC) develops in 30% of patients, presents with metastasis in the skeleton and soft tissues, and is currently incurable. Our group conclusively showed that skeletal metastases in prostate cancer (PCa) patients harbor approximately 30% of tumor cells lacking the Androgen Receptor (AR), a nuclear receptor widely considered the major driver of this disease. Furthermore, we discovered that AR-negative PCa cells express Interleukin-1beta (IL-1[beta]), whereas AR-positive cells lack this cytokine. Pre-clinical work in our lab has revealed that IL-1[beta] serves a pro-metastatic role for AR-negative PCa cells. In addition, AR-negative cells expressing IL-1[beta] promote the growth of AR-negative/IL-1[beta]-negative cells, which lack independent bone-metastatic potential. In the context of androgen ablation, a therapeutic strategy applied to all PCa patients, we found that AR-negative PCa cells can support the growth of hormone-dependent AR-positive cells by promoting their shift to an androgen-independent phenotype characterized by an low AR, high PMEPA, high AKR1C3 molecular signature. In vitro studies confirmed that 1. IL-1[beta] directly regulates expression of AKR1C3, a steroidogenic enzyme which supports the autonomous synthesis of testosterone, by an NF-[kappa]B-independent mechanism and that 2. de novoexpression of IL-1[beta] in cells previously lacking this cytokine is induced by inhibition of the AR signaling axis. These studies elucidate the role of IL-1[beta] in the context of CRPC and may provide conceptual ground for shifting the current treatment paradigms towards therapeutic targeting of AR-negative cells in combination with the current standard of care.
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Details
- Title
- Heterogeneity in androgen receptor and Interleukin-1 beta expression by prostate cancer cells in skeletal metastases
- Creators
- Asurayya Worrede - DU
- Contributors
- Alessandro Fatatis (Advisor) - Drexel University (1970-)Seena Ajit (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 151 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 9433; 991014632659204721