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Rationale and clinical implication of combined chemotherapy with cisplatin and oestrogen in prostate cancer: primary evidence based on methylation analysis of oestrogen receptor‐α
Author(s) -
MoriyamaGonda Nobuko,
Shiina Hiroaki,
Terashima Masaharu,
Satoh Kazumi,
Igawa Mikio
Publication year - 2008
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2007.07256.x
Subject(s) - lncap , dna methylation , cisplatin , prostate cancer , bisulfite sequencing , cancer research , methylation , biology , microbiology and biotechnology , medicine , cancer , gene expression , chemotherapy , dna , gene , biochemistry
OBJECTIVE To determine whether oestrogen enhances platinum sensitivity, and if promoter CpG methylation of the oestrogen receptor‐α (ER‐α) gene determines the potential of cisplatin‐induced apoptosis in prostate cancer, as the high‐mobility group 1 (HMG1) preferentially binds to cisplatin‐modified DNA and is up‐regulated after oestrogen treatment in breast cancer cell line MCF‐7. MATERIALS AND METHODS The study comprised prostate cancer cell lines (LNCaP and PC‐3), 156 pathologically confirmed 156 radical prostatectomy samples and eight hormone‐refractory prostate cancer (HRPC) samples (from needle biopsy). Expression of HMG1 in cell lines was analysed by Western blotting or differential reverse‐transcription‐polymerase chain reaction (PCR). The methylation status of ER‐α was analysed by methylation‐specific PCR using bisulphite DNA as a template or bisulphite DNA sequencing. RESULTS In LNCaP cells, treatment with oestrogen increased HMG1 expression and co‐treatment with cisplatin and oestrogen reduced cell viability by accelerating apoptosis, compared with cisplatin alone. However, in PC‐3, oestrogen did not up‐regulate HMG1 or accelerate the cisplatin‐induced apoptosis. Although ER‐β was expressed in both LNCaP and PC‐3, ER‐α was expressed only in LNCaP. Bisulphite DNA sequencing of the ER‐α promoter showed partial methylation in LNCaP but complete methylation in PC‐3. ER‐α AS transfection diminished the cisplatin‐induced apoptosis in oestrogen‐treated LNCaP cells. In clinical samples there was ER‐α hypermethylation in 40% of prostate cancers this correlated with Gleason score (GS, 31% for GS < 7, 50% for GS = 7 and 56% for GS > 7). In addition, five of eight HRPC samples showed ER‐α hypermethylation. CONCLUSION These findings suggest that HMG1 induction as an enhancer of platinum sensitivity is mediated through interaction between oestrogen and ER‐α. As CpG hypermethylation of the ER‐α promoter is a frequent event in aggressive prostate cancer, negative conversion of ER‐α methylation is essential to achieve the most beneficial effect when combined chemotherapy of cisplatin with oestrogen is used in patients with prostate cancer.