ABSTRACT
The long arm of chromosome 8 is one of the most common regions of amplification in cancers of several organs, especially carcinomas of the breast and prostate. TRPS1, MYC and EIF3S3 genes are located in one of the minimal regions of amplification, 8q23-q24, and have been suggested to be the target genes of the amplification. Here, our goal was to study copy number and expression of the three genes in order to investigate the significance of the genes in breast and prostate cancer. By using fluorescence in situ hybridisation (FISH), we first found that TRPS1 and EIF3S3 were amplified together in about one-third of hormone-refractory prostate carcinomas. Next, we analysed the mRNA expression of the three genes by real-time quantitative RT-PCR and the gene copy number by FISH in six breast and five prostate cancer cell lines. Breast cancer cell line, SK-Br-3, which contained the highest copy number of all three genes, showed overexpression of only EIF3S3. Finally, the expression levels of TRPS1, EIF3S3 and MYC were measured in freshly frozen clinical samples of benign prostate hyperplasia (BPH), as well as untreated and hormone-refractory prostate carcinoma. The TRPS1 and MYC expression levels were similar in all prostate tumour groups, whereas EIF3S3 expression was higher (P=0.029) in prostate carcinomas compared to BPH. The data suggest that the expression of EIF3S3 is increased in prostate cancer, and that one of the mechanisms underlying the overexpression is the amplification of the gene.
Subject(s)
Breast Neoplasms/genetics , DNA-Binding Proteins , Eukaryotic Initiation Factor-3/genetics , Gene Dosage , Genes, myc/physiology , Neoplasm Proteins/genetics , Prostatic Neoplasms/genetics , Breast Neoplasms/metabolism , Chromosomes, Human, Pair 8/genetics , DNA Probes/genetics , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Eukaryotic Initiation Factor-3/metabolism , Female , Gene Amplification/genetics , Humans , In Situ Hybridization, Fluorescence , Male , Neoplasm Proteins/metabolism , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/metabolism , Neoplasms, Hormone-Dependent/genetics , Neoplasms, Hormone-Dependent/metabolism , Prostatic Hyperplasia/genetics , Prostatic Hyperplasia/metabolism , Prostatic Neoplasms/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Repressor Proteins , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors , Tumor Cells, CulturedABSTRACT
The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is a key player in the regulation of bone mineralization and calcium homeostasis. In addition, 1,25-(OH)2D3 has antiproliferative and prodifferentiation effects on various cells in vitro and in vivo. The growth-inhibitory properties of 1,25-(OH)2D3 could be harnessed in the treatment of cancer. However, its use as an anti-cancer drug is limited because of the calcemic effects of pharmacological doses. In an attempt to dissociate the antiproliferative and calcemic effects, numerous vitamin D3 analogs were developed. The mechanisms by which 1,25-(OH)2D3 and 1,25-(OH)2D3 analogs exert their growth-inhibitory effects are not clear but include effects on cell differentiation, apoptosis, cell cycle regulation, metastases, and angiogenesis. In the current review aspects involved in the tumor suppressive activity of 1,25-(OH)2D3 and 1,25-(OH)2D3 analogs will be addressed. The use of vitamin D3 compounds, alone or in combination with other drugs, in cancer treatment and the potential drawbacks will also be discussed.
Subject(s)
Neoplasms/drug therapy , Vitamin D/analogs & derivatives , Vitamin D/therapeutic use , Animals , Cell Death/drug effects , Cell Death/physiology , Cell Differentiation/drug effects , Cell Differentiation/physiology , Clinical Trials as Topic/statistics & numerical data , Humans , Vitamin D/pharmacologyABSTRACT
Expression of death-signaling genes induces many biochemical cascades resulting in elimination of cells via apoptosis or programmed cell death. GC79/TRPS1 is a novel apoptosis associated gene that encodes a multitype zinc finger GATA-type transcription factor. Expression of GC79/TRPS1 is repressed in the rat ventral prostate and significantly elevated after androgen withdrawal by castration. Castration leads to regression of the prostate caused by apoptosis of androgen-dependent prostate cells. Prostate cancer consists of androgen-dependent and androgen-independent cells. The androgen-independent cells, usually present in the prostate of advanced prostate cancer patients do not have the ability to undergo apoptosis after androgen withdrawal. GC79/TRPS1 expression in androgen-dependent prostate cancer cells is repressed by androgens, while GC79/TRPS1 expression is hardly detectable in androgen-independent prostate cancer cells under cell culture conditions. This suggests that lack of GC79/TRPS1 expression could be a mechanism for the inability to induce the apoptotic pathway in androgen-independent prostate cancer cells after androgen withdrawal. This review will focus on the current knowlegde of the structure and function of GC79/TRPS1, a novel androgen-repressible apoptosis gene.
