Pattern of Somatic Androgen Receptor Gene Mutations in Patients with Hormone-Refractory Prostate Cancer

Abstract

SUMMARY:Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated with orchiectomy, estrogens, or a combination of orchiectomy and estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the tumors, respectively. Two (50%) tumors with AR amplification also had missense mutation of the gene. Four of five (80%) cancers that were treated with a combination of orchiectomy and estramustine phosphate had a mutation clustered at codons 514 to 533 in the N-terminal domain of AR. In functional studies, these mutations did not render AR more sensitive to testosterone, dihydrotestosterone, androstenedione, or ␤-estradiol. Tumors treated by orchiectomy had mutations predominantly in the ligand-binding domain. In summary, we found molecular alterations of AR in more than half of the prostate carcinomas that recurred locally. Some tumors developed both aberrations, possibly enhancing the cancer cell to respond efficiently to low levels of androgens. Furthermore, localization of point mutations in AR seems to be influenced by the type of treatment. (Lab Invest 2002, 82:1591-1598. P rostate cancer (CaP) is the most common male malignancy in the Western world, and its prognosis greatly depends on at which stage the disease is diagnosed. Even in the era of prostate specific antigen (PSA) screening, advanced disease is diagnosed in 20 to 40% of patients with CaP when cure by radical prostatectomy or radiotherapy is not considered possible anymore. In addition, recurrence rates of CaP after radical surgery or radiotherapy approach 25 to 50% (Dennis and Griffiths, 2000;Määttänen et al, 1999;Scardino et al, 1994). For these patients, androgen deprivation therapy (ADT) remains the only effective palliative treatment. ADT is generally achieved by either surgical or chemical castration, but for patients with widespread, metastasized disease, the cytotoxic drug estramustine phosphate (EMP) is occasionally combined with ADT (Kuhn et al, 1994;Murphy et al, 1986). Although all ADTs are initially effective, in most patients, CaP progresses within months or a few years (Dennis and Griffiths, 2000;Scardino et al, 1994). Molecular mechanisms of ADT failure are not comprehensively known. Previous studies have suggested a link between androgen receptor (AR) gene and ADT failure (Culig et al, 1993;Elo et al, 1995;Koivisto et al, 1997;Schoenberg et al, 1994;Suzuki et al, 1993Suzuki et al, , 1996Taplin et al, 1995Taplin et al, , 1999Visakorpi et al, 1995;Wallen et al, 1999), and two main mechanisms by which CaP cells could adapt and sensitize AR signaling pathway for growth in low levels of androgens have been proposed. First, AR gene amplification has been shown to lead to increased expr...

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

“…29,30,[39][40][41] The type of treatment given was also shown to influence the kind of mutation seen. 42 Since reports have shown that mutations are present in 20-40% of the advanced PCAs before therapy, 30,31 it could be hypothesized that the mutations were not induced by therapy but were pre-existent. Therefore, certain clones that can grow in the absence or presence of very little androgens are selected for growth during androgen withdrawal and grow aggressively to reestablish the disease.…”

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

“…4,9 Much of our understanding of AR function is derived from the study of somatic missense mutations in the AR gene in patients with androgen insensitivity syndrome (inactivating mutations) or in primary, recurrent and metastatic prostate tumors and cell lines. [10][11][12] AR variants identified in clinical prostate tumors typically exhibit promiscuous activation by nonandrogenic ligands and/or enhanced transactivation capacity due to altered interactions with coregulators. 13 The prototypical example of AR promiscuity is AR-T877A (T857A in mice), a variant expressed in the LNCaP prostate cancer cell line that is activated by estrogen, progesterone and the AR antagonist, hydroxyflutamide, in addition to androgens.…”

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

“…9,10 Thus AR can be active even in low androgen environment. AR mutations cluster in an area that defines AR protein interactions, [11][12][13] they are rare in local disease [14][15][16] but frequent in metastases where they enable binding with estradiols, glucocorticoids and anti-androgens 11,17 (reviewed in Ref. 17).…”