Author ORCID Identifier
orcid.org/0000-0003-0030-2511
Date of Graduation
5-2017
Document Type
Dissertation (PhD)
Program Affiliation
Epigenetics and Molecular Carcinogenesis
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dean Tang
Committee Member
Mark Bedford
Committee Member
Taiping Chen
Committee Member
Sharon Dent
Committee Member
Rick Finch
Abstract
Androgen receptor (AR) plays an important role in prostate cancer (PCa) development and has been the main therapeutic target in advanced PCa. AR expression is heterogeneous in both primary PCa and castration resistant prostate cancer (CRPC). However, the functional significance of AR heterogeneity in regulating PCa biology and response to androgen/AR-targeted therapies remains unclear. The overarching hypothesis for my Ph.D is that AR heterogeneity contributes to PCa development, progression, and therapy resistance. A more specific postulate is that PCa cells expressing AR (i.e, AR+) and PCa cells expressing little AR (i.e, AR-/lo) possess intrinsically distinct biological and tumorigenic properties as well as sensitivities to AR-targeting therapies. Here I tested my hypothesis by generating RFP-tagged AR+ LNCaP clones with zinc finger nucleases (ZFNs) and isogenic AR knockout (AR-KO) LNCaP clones with CRISPR-cas9 technology. With the novel genetically matched clones, we demonstrate that the AR+ and AR-KO clonal LNCaP cells manifest contrasting tumor-regenerating capacities and responses to castration and AR antagonists. Specifically, AR+ LNCaP cells are highly tumorigenic in androgen-dependent (AD) environment and are exquisitely sensitive to androgen-deprivation therapy (ADT). On the contrary, AR-KO LNCaP cells possess high tumor-initiating and tumor-propagating capabilities in androgen-ablated environment. Further, AR-KO LNCaP cells are resistant to the current AR antagonist enzalutamide. Thus, our study links AR heterogeneity to distinct castration and enzalutamide responses and suggests the urgency in developing novel therapeutics to target AR-/lo PCa cells/clones.
Keywords
androgen receptor, prostate cancer, castration resistance, enzalutamide, cancer cell heterogeneity