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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2011

01-11-2011 | Preclinical study

Role of PTEN promoter methylation in tamoxifen-resistant breast cancer cells

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

Published in: Breast Cancer Research and Treatment | Issue 1/2011

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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.
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Metadata
Title
Role of PTEN promoter methylation in tamoxifen-resistant breast cancer cells
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
Publication date
01-11-2011
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-010-1304-2

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