In vivo amplification of the androgen receptor gene and progression of human prostate cancer

Abstract

Overexpression of amplified genes is often associated with the acquisition of resistance to cancer therapeutic agents in vitro. We have identified a similar molecular mechanism in vivo for endocrine treatment failure in human prostate cancer which involves amplification of the androgen receptor (AR) gene. Comparative genomic hybridization shows that amplification of the Xq11-q13 region (the location), is common in tumours recurring during androgen deprivation therapy. We found high-level AR amplification in seven of 23 (30%) recurrent tumours, but in none of the specimens taken from the same patients prior to therapy. Our results suggest that AR amplification emerges during androgen deprivation therapy by facilitating tumour cell growth in low androgen concentrations.

Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer

“…Androgen receptor gene amplifications are uncommon in hormone-sensitive tumours and are present in 20 -30% of hormoneresistant tumours (Visakorpi et al, 1995;Koivisto et al, 1997;Bubendorf et al, 1999;Miyoshi et al, 2000;Edwards et al, 2001). In the present study, we investigated AR amplification, AR protein expression and PSA expression in paired hormone-sensitive and hormone-resistant tumours from the same patient with documented initial responses to androgen deprivation therapy.…”

“…In the light of this observation it is possible, though at present unproven and to our view unlikely, that AR amplification does not mediate hormone resistance. It is hypothesised that AR gene amplification is involved in the development of hormone-resistant prostate cancer due to amplification, resulting in an increase in AR protein expression (Visakorpi et al, 1995). Real-time RT -PCR demonstrated that even one additional copy of the AR gene may increase AR expression (Linja et al, 2001), suggesting that even a small increase in relative gene dosage could have biological significance.…”

“…This effect is however, transient (Newling et al, 1997) with the majority of patients developing androgen resistance (Newling et al, 1997). The mechanisms involved with the development of resistance are poorly understood, but AR mutations (Avila et al, 2001), AR amplification (Visakorpi et al, 1995), increased AR expression (Gregory et al, 1998) and activation of the AR by interaction with other signalling pathways have been implicated (Culig et al, 1998).…”

Targeted therapy of cancer: new roles for pathologists—prostate cancer

“…16,17 Amplification of the AR gene was seen in approximately 20-30% of all HR tumors. [18][19][20][21][22][23] In addition, there was heterogeneity in the amplification seen within tumors. 22 These studies indicated that since amplification is seen in refractory tumors, only the clones having the amplifications would be selected for further growth in a low-androgen environment, and would accumulate the chromosomal changes with time to establish aggressive disease.…”

Beyond Castration—Defining Future Directions in the Hormonal Treatment of Prostate Cancer

“…The preclinical basis for this is manifold: (1) a frequent change following the development of metastatic castration resistant disease is the mutation, gene amplification and/or overexpression androgen receptor (AR) [9]; (2) several studies utilising diverse methodologies suggest that it is the intracrine and paracrine effects of in situ androgen synthesis or circulating adrenal derived steroid precursors that significantly contribute to prostate cancer growth [10] and (3) there appear to be multiple abnormalities within the AR pathway, involving coactivators and corepressors (~100% in CRPC metastatic samples) that predispose to AR pathway activation [11]. To date, there are broadly two new classes of hormonally active drugs in development: more effective AR antagonists (such as MDV3100, ARN-509, TOK-001) and inhibitors of the androgen biosynthetic pathway [such as abiraterone, TAK-700 (orteronel)].…”