Gene Expression Analysis of Human Prostate Carcinoma during Hormonal Therapy Identifies Androgen-Responsive Genes and Mechanisms of Therapy Resistance

Abstract

The androgen-signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease. We performed a genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance. Six hundred and fifty-four of 63,175 probe sets detected significant expression changes after 3 months of treatment with goserelin and flutamide. This included 149 genes that were also differentially expressed 36 hours after androgen withdrawal in LNCaP cells. These genes reflect the physiological changes that occur in treated tumors and include potential direct targets of the androgen receptor. Expression profiles of androgen ablation-resistant tumors demonstrated that many of the gene expression changes detected during therapy were no longer present suggesting a reactivation of the androgen response pathway in the absence of exogenous hormone. Therapy resistance was associated with differential expression of a unique set of genes that reflect potential mechanisms of reactivation. Specifically an up-regulation of the androgen receptor and key enzymes for steroid biosynthesis suggest that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. The specific pathways of reactivation provide opportunities for classification of resistant tumors and targeted therapies.

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

“…The second cohort consisted of patients treated for prostate cancer at MSKCC and consisted of prostatic tissues obtained from therapeutic or diagnostic procedures performed as part of routine clinical management of disease, hereafter referred to as the Holzbeierlein cohort. 26 This cohort was composed of 23 primary prostate tumor samples from men who received no therapy before surgery [eight of which had subsequent biochemical recurrence (BCR)], 17 primary prostate tumor samples from men who received 3 months androgen deprivation therapy (ADT) before surgery, and nine metastatic prostate cancer samples, 3 of which had progressed after ADT (Supporting Information Table 2). Expression profiling of the samples in this cohort was carried out using Affymetrix U95 human gene arrays.…”

Androgen receptor signalling in prostate: Effects of stromal factors on normal and cancer stem cells

“…The androgen receptor signalling pathway is critical to the development and progression of CaP and BPH (Holzbeierlein et al, 2004). The AR mediates male sexual differentiation during development, sperm production from puberty, and maintenance of normal prostate (Heinlein and Chang, 2004).…”

Abiraterone acetate, a first-in-class CYP17 inhibitor, establishes a new treatment paradigm in castration-resistant prostate cancer

“…Evidence has accumulated in recent years for each of these mechanisms, suggesting that these are not mutually exclusive and that substantial hetero geneity is present [2]. It is becoming clear, for example, that ADT causes growth arrest, but does not induce significant apoptosis in prostate cancer cells [7].…”

“…More recent in vitro evidence had shown that a subset of prostate cancer cells that survive androgendepleted conditions express increased levels of stem cell markers and are able to repopulate the tumor, possibly through adaptive AR pathway changes [9]. These adaptive changes include AR overexpression [6,10] or gain-of-function mutations [2,4] that increase receptor sensitivity to circulating androgens. Alternatively, these mutations can also allow AR to be activated by noncanonical ligands [2], such as other steroids (e.g., progesterone) [1], or even by agents initially used as antiandrogens in the same Editorial patient (e.g., flutamide and bicalutamide).…”