FISH Analysis of Gene Aberrations (MYC, CCND1, ERBB2, RB, and AR) in Advanced Prostatic Carcinomas Before and After Androgen Deprivation Therapy

Kaltz-Wittmer, Christine; Klenk, Ulrich; Glaessgen, Axel; Aust, Daniela E.; Diebold, Joachim; Löhrs, U.; Baretton, Gustavo

doi:10.1038/labinvest.3780152

Cited by 83 publications

(61 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We previously reported AR amplification and overexpression in 30% of the CaPs that recurred during ADT (Bubendorf et al, 1999;Koivisto et al, 1997;Visakorpi et al, 1995). In the present study, the prevalence of AR gene amplification was 25%, which is in line with reports from other laboratories (Kaltz-Wittmer et al, 2000;Miyoshi et al, 2000). The tumors with amplification were equally distributed among the therapy groups, suggesting that orchiectomy, estrogen therapy, and a combination therapy of orchiectomy and EMP are able to cause such a reduction in intraprostatic DHT levels that the growth of malignant cells is disturbed and only cell clones with selective growth advantages, such as extra AR copies, are survived under the androgendeficient milieu.…”

Section: Discussionsupporting

confidence: 83%

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

Hyytinen

Haapala

Thompson

et al. 2002

Laboratory Investigation

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 83%

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

Hyytinen

Haapala

Thompson

et al. 2002

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Prostate cancer is the most common noncutaneous malignancy diagnosed in American men (25), but there is only a limited understanding of its genetic and molecular basis (26). Different studies have shown that c-Myc mRNA is commonly overexpressed in hyperplasic and malignant prostate (27), and the c-Myc gene is amplified in between 11% and 40% of prostate cancers in different studies (28)(29)(30). Although c-Myc amplification has been mainly associated with metastatic progression, c-Myc is also amplified at lower levels in initial stages of prostate carcinogenesis (30).…”

Section: Introductionmentioning

confidence: 99%

Immortalization of Primary Human Prostate Epithelial Cells by c-Myc

et al. 2005

View full text Add to dashboard Cite

“…Cyclin D1 null mice exhibit deficiencies in mammary gland development, including specific defects in alveolar growth [75,76], a phenotype similar to adult female mice lacking PR-B [77]. Cyclin D1 mRNA and protein levels increase in response to estrogen, progesterone, or androgen treatment [17,78,79] and cyclin D1 is frequently elevated in breast and prostate cancers [80,81]. Interestingly, the D1a isoform of cyclin D1 acts as an androgen-induced transcriptional repressor of AR via direct binding to the AR amino-terminus [82].…”

Section: Integrated Sr Actions In Gene Expressionmentioning

confidence: 99%

Integration of progesterone receptor action with rapid signaling events in breast cancer models

Lange

2008

The Journal of Steroid Biochemistry and Molecular Biology

View full text Add to dashboard Cite

Recent discoveries suggest that several protein kinases are rapidly activated in response to ligand binding to cytoplasmic steroid hormone receptors (SRs), including progesterone receptors (PRs). Thus, PRs act as ligand-activated transcription factor "sensors" for growth factor-initiated signaling pathways in hormonally regulated tissues, such as the breast. Induction of rapid signaling upon progestin-binding to PR-B provides a means to ensure that receptors and co-regulators are appropriately phosphorylated as part of optimal transcription complexes. Alternatively, PR-B activated kinase cascades provide additional avenues for progestin-regulated gene expression independent of PR nuclear action. Herein, an overview of progesterone/PR and signaling cross-talk in breast cancer models is provided. Kinases are emerging as key mediators of PR action. Cross-talk between SR and membrane-initiated signaling events suggests a mechanism for coordinate regulation of gene subsets by mitogenic stimuli in hormonally responsive normal tissues, and is suspected to contribute to cancer biology.

show abstract

FISH Analysis of Gene Aberrations (MYC, CCND1, ERBB2, RB, and AR) in Advanced Prostatic Carcinomas Before and After Androgen Deprivation Therapy

Cited by 83 publications

References 22 publications

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

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

Immortalization of Primary Human Prostate Epithelial Cells by c-Myc

Integration of progesterone receptor action with rapid signaling events in breast cancer models

Contact Info

Product

Resources

About