Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients

Miyoshi, Yasuhide; Uemura, Hiroji; Fujinami, Kiyoshi; Mikata, Kunihisa; Harada, Masaoki; Kitamura, Hitoshi; Koizumi, Yoko; Kubota, Yoshinobu

doi:10.1002/(sici)1097-0045(20000515)43:3<225::aid-pros9>3.0.co;2-7

Cited by 62 publications

(45 citation statements)

References 20 publications

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“…Therefore, 65% of the recurrent cases investigated had increased AR copy numbers compared with normal prostate gland cells [9]. These ®ndings have since been con®rmed by several studies reporting ampli®cation of the AR in 20±30% and polysomy of chromosome X in 35±80% of recurrent tumours [9,11,12]. These data have been used to suggest that an increase in AR copy number is involved in the development of hormone-refractory prostate cancer.…”

Section: Discussioncontrasting

confidence: 94%

“…Several studies supporting this hypothesis investigated levels of AR gene ampli®cations and aneusomy of chromosome X in recurrent tumours from patients who initially responded to androgen-deprivation therapy [4,9,11,12]. Visakorpi et al [9] reported that 30% of recurrent tumour specimens resistant to androgendeprivation therapy had AR gene ampli®cation.…”

Section: Discussionmentioning

confidence: 99%

“…The results cast doubt on the role of AR ampli®cation or duplication as mechanisms of hormone escape. Although 65% of recurrent tumours had an increase in AR copy number, consistent with values previously reported [9,11,12], 35% of them also had increased copies of AR in the pretreatment tumours. Despite this, each of these patients had a documented response to antiandrogens (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Amplification of the androgen receptor may not explain the development of androgen‐independent prostate cancer

Edwards¹,

Krishna²,

Mukherjee³

et al. 2001

BJU International

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Objective To examine the role of androgen receptor (AR) gene amplification and aneusomy of the X chromosome in the development of antiandrogen‐resistant prostate cancer. Patients and methods Twenty patients with prostate cancer resistant to androgen‐deprivation therapy were selected for study. The records of patients with tumours before and after antiandrogen therapy, and with a full clinical follow‐up, were retrieved. AR gene amplification and X chromosome copy number were assessed by fluorescence in situ hybridization using a labelled probe at locus Xq11–13 for the AR gene and a labelled α‐satellite probe for the X chromosome. At least 20 nuclei were scored over three tumour areas by two independent observers. Results Aneusomy of the X chromosome was reported respectively in seven (35%) and 11 (55%) tumours before and after hormone relapse, the AR gene copy number was increased in seven (35%) and 13 (65%), respectively, and AR gene amplification was detected in one (5%) and three (15%), respectively. Neither increased AR copy number nor AR amplification in primary tumours precluded a biological response to androgen‐deprivation therapy. Conclusion The rate of AR gene amplification is too low to be solely responsible for the development of antiandrogen‐resistant prostate cancer. Also, the presence of amplified AR and cells aneusomic for the X chromosome in primary tumours that respond to androgen‐deprivation therapy suggests that an increase in AR gene copy number does not prevent a tumour from responding to this therapy. Therefore other mechanisms which could cause hormone‐refractory prostate cancer must be investigated before it is understood why so many patients relapse with this disease.

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Section: Discussioncontrasting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Amplification of the androgen receptor may not explain the development of androgen‐independent prostate cancer

Edwards¹,

Krishna²,

Mukherjee³

et al. 2001

BJU International

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“…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.…”

Section: Discussionmentioning

confidence: 88%

“…AR gene copy number has been demonstrated to correlate positively with PSA expression (Koivisto and Helin 1999). Polysomy of chromosome X ranges from 42 to 60% and amplification of the AR gene ranges from 20 to 30% in hormone-resistant prostate tumours (Koivisto et al, 1997;Bubendorf et al, 1999;Miyoshi et al, 2000;Edwards et al, 2001). However, there is still no clear investigation into AR gene amplification and AR protein expression in hormone-sensitive and hormoneresistant prostate cancer, using paired tumours from the same patient.…”

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confidence: 99%

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

et al. 2003

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This study examined androgen receptor (AR) gene amplification and protein expression in 102 matched paired hormone sensitive and resistant tumours from 51 patients. AR gene amplification and X chromosome copy number were assessed by fluorescent in situ hybridisation, and protein expression was assessed by immunohistochemistry. All tumours were stained for PSA protein expression. Significantly more tumours exhibited AR amplification following the development of hormone resistance (20%, 10 out of 49) compared to matched hormone-sensitive tumours from the same patient (2%, one out of 48) (P ¼ 0.0085). The level of AR expression was significantly higher in hormone-resistant tumours compared to matched hormone-sensitive tumours from the same patient (130, interquartile range, 55 -167 vs 94.5 interquartile range, 55 -120, P ¼ 0.019). AR expression levels in hormone-resistant tumours with and without AR amplification were not significantly different. However, an increase in AR expression was seen with the development of AR amplification in paired tumours. The rate of AR gene amplification and/or an increase in AR protein expression during androgen resistant is too low to wholly explain the development of androgen resistance. Alternative mechanisms for modulating the function of the AR, or other signalling pathways, must be considered as key factors in the development of hormoneresistant prostate.

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The androgen receptor gene and its influence on the development and progression of prostate cancer

2001

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Prostate adenocarcinoma has the highest incidence of any malignancy and is the second leading cause of cancer-related deaths in men in industrialized countries. The development and progression of prostate cancer are dependent on testosterone and dihydrotestosterone; the androgen receptor is the vehicle through which these androgens exert their regulation on prostate cellular proliferation and differentiation. As a result, much effort has been devoted to elucidating the role of the androgen receptor in prostate cancer. The CAG and GGN trinucleotide repeats in exon 1 of the androgen receptor gene have been linked to prostate cancer risk and progression in some studies. Also, androgen receptor gene amplification may be a mechanism of prostate cancer cell adaptation to hormonal therapy. In addition, androgen receptor somatic mutations can result in receptors that have altered binding specificity when compared with wild-type receptors and heightened affinity for hormones other than testosterone and dihydrotestosterone. Gene amplification and somatic mutations, coupled with the fact that various growth factors have been shown to stimulate androgen receptor activity independently of androgens, may enable prostate cancer cells to grow despite testicular-androgen ablation. Unfortunately, current medical therapy for metastatic prostate cancer is deficient, hormone-refractory prostate cancer is a major obstacle in treatment, and, as a result, prostate cancer mortality is still significant. Further study of the function of the androgen receptor will offer a better understanding of prostate cancer pathogenesis and progression, aiding the development of more effective treatments for this disease.

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Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients

Cited by 62 publications

References 20 publications

Amplification of the androgen receptor may not explain the development of androgen‐independent prostate cancer

Amplification of the androgen receptor may not explain the development of androgen‐independent prostate cancer

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

The androgen receptor gene and its influence on the development and progression of prostate cancer

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