title: Role of PTEN promoter methylation in tamoxifen-resistant breast cancer cells.
abstract: Tamoxifen (TAM) resistance is a serious clinical problem in the treatment of breast cancer. Here, we found that S-adenosylmethionine (SAM) and DNA methyltransferase1 (DNMT1) expression are up-regulated in TAM-resistant breast cancer (TAMR-MCF-7) cells. We further focused on whether increased SAM with DNMT1 overexpression in TAMR-MCF-7 cells lead to aberrant methylation of the PTEN gene promoter and its therapeutic potential. Methylation-specific PCR analyses revealed that two sites within the PTEN promoters were methylated in TAMR-MCF-7 cells, which resulted in down-regulation of PTEN expression and increase in Akt phosphorylation. Both the loss of PTEN expression and the increased Akt phosphorylation in TAMR-MCF-7 cells were completely reversed by 5-aza-2'-deoxycytidine (5-Aza), a DNMT inhibitor. 5-Aza inhibited the basal cell proliferation rate of TAMR-MCF-7 cells and intraperitoneal injection of 5-Aza significantly suppressed TAMR-MCF-7 tumor growth in a xenograft study. Immunohistochemistry showed that PTEN expression in TAM-resistant human breast cancer tissues was lower than in TAM-responsive cases. These results suggest that methylation of the PTEN promoter related to both SAM increase and DNMT1 activation contributes to persistent Akt activation and are potential therapeutic targets for reversing TAM resistance in breast cancer.
authors.affiliation: BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, 501-759, South Korea.
authors.forename: Nguyen Thi Thuy
authors.initials: NT
authors.lastname: Phuong
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Lim
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.forename: Kwang Yeol
authors.initials: KY
authors.lastname: Lee
authors.forename: Sang-Gun
authors.initials: SG
authors.lastname: Ahn
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Yoon
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012436:S-Adenosylmethionine / Q000096:biosynthesis; D013629:Tamoxifen / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D000077209:Decitabine; D012436:S-Adenosylmethionine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D001374:Azacitidine