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: Nguyen Thi Thuy Phuong, Sang Kyum Kim, Sung Chul Lim, Hyung Sik Kim, Tae Hyung Kim, Kwang Yeol Lee, Sang-Gun Ahn, Jung-Hoon Yoon, Keon Wook Kang
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 130 Issue 1 Pg. 73-83 (Nov 2011) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 21170675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Hormonal
• Tamoxifen
• Decitabine
• S-Adenosylmethionine
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases
• DNMT1 protein, human
• Dnmt1 protein, mouse
• Phosphatidylinositol 3-Kinases
• Oncogene Protein v-akt
• PTEN Phosphohydrolase
• PTEN protein, human
• Azacitidine

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Antineoplastic Agents, Hormonal (pharmacology)
• Apoptosis (drug effects)
• Azacitidine (administration & dosage, analogs & derivatives, pharmacology)
• Breast Neoplasms (drug therapy, enzymology, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases (metabolism)
• DNA Methylation
• Decitabine
• Drug Resistance, Neoplasm (genetics)
• Enzyme Activation (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Oncogene Protein v-akt (metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Promoter Regions, Genetic
• S-Adenosylmethionine (biosynthesis)
• Tamoxifen (pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays