| Summary: | Prostate cancer is one of the most common cancers diagnosed and the second leading
cause of cancer related death in North American men. The prostate is dependent on
male-sex hormones (androgens) for differentiation and growth. Prostate cancer derived
from prostatic epithelial cells is likewise dependent on androgens for survival. Androgen
deprivation therapy (ADT) through pharmacological methods is currently the most
effective treatment for disease no longer localized to the prostate gland. ADT offers a
temporary remission, but only delays disease progression as the cancer cells adapt to
survive and proliferate in castrate levels of circulating androgens. There is mounting
evidence to suggest that intratumoral androgens acting through the androgen receptor
(AR) continue to play a critical role in castration resistant prostate cancer (CRPC)
progression.
Recent advances in RNA profiling technologies are revealing a more complex picture of
the human transcriptome. Alternative splice variants of protein-coding mRNAs and nonprotein-
coding regulatory RNAs (ncRNA) were identified in this research that are
expressed in prostate and prostate cancer cells. A custom 180K microarray was
designed to profile the expression of the identified prostate RNAs, ncRNAs, and other
reference RNAs. The custom microarray was used to profile expression after treatment
in vitro with androgens and anti-androgens in the LNCaP prostate cancer cell line. The
expression of the identified androgen regulated RNAs were examined in vivo after
castration and during progression to CRPC in LNCaP xenograft tumors. The research
presented is an integrative analysis of in vitro and in vivo expression profiles with ARDNA
interactions detected by AR ChIP-seq and microRNAs detected by small RNA
sequencing. The integrated expression profiles suggest a different androgen regulated
transcriptional program in CRPC from that seen in treatment naive tumors. Several
unexpected findings were revealed including a cell cycle related difference between
synthetic androgen, R1881, and physiological androgen, DHT; RNAs increased by the
anti-androgen, MDV3100, and not bicalutamide; and the use of alternative 3‟ UTRs
following castration in the in vivo model. The identified reference and novel androgen
regulated RNAs may inform on the mechanism underlying androgen deprivation
therapy, anti-androgen response, and the progression to CRPC.
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