Promoter methylation of RASSF1A modulates the effect of the microtubule-targeting agent docetaxel in breast cancer

Gil,Eun  Young; Jo,Uk  Hyun; Jeong,Hoiseon; Whang,Young  Mi; Woo,Ok  Hee; Cho,Kyu  Ran; Seo,Jae  Hong; Kim,Aeree; Lee,Eun  Sook; Koh,Insong; Kim,Yeul  Hong; Park,Kyong  Hwa

doi:10.3892/ijo.2012.1470

Promoter methylation of RASSF1A modulates the effect of the microtubule-targeting agent docetaxel in breast cancer

Authors:
- Eun Young Gil
- Uk Hyun Jo
- Hoiseon Jeong
- Young Mi Whang
- Ok Hee Woo
- Kyu Ran Cho
- Jae Hong Seo
- Aeree Kim
- Eun Sook Lee
- Insong Koh
- Yeul Hong Kim
- Kyong Hwa Park
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Affiliations: Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea, Division of Oncology/Hematology, Department of Pathology, Korea University College of Medicine, Seoul, Republic of Korea, Division of Oncology/Hematology, Department of Radiology, Korea University College of Medicine, Seoul, Republic of Korea, Division of Oncology/Hematology, Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea, Department of Physiology, College of Medicine, Hanyang University, Seoul, Republic of Korea
Published online on: May 10, 2012 https://doi.org/10.3892/ijo.2012.1470
Pages: 611-620

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Abstract

Docetaxel is one of the most commonly used chemotherapeutic agents in breast cancer. To avert from significant toxicities with no clinical benefit, identification of predictive markers for response is one of the most important unsolved clinical needs. Therefore, the potential associations of RASSF1A hypermethylation and response to docetaxel-based chemotherapy were evaluated, and the underlying mechanism was studied. The expression of RASSF1A in breast cancer cell lines and tissues of normal breast, ductal carcinoma in situ (DCIS), and breast cancer (n=45) was analyzed by immunohistochemistry and western blot analysis. Immunohistochemical staining showed that the expression of RASSF1A was frequently lost in primary breast cancers and human breast cancer cell lines, while normal breast tissues or DCIS displayed moderate to strong expression. Furthermore, quantitative methylation analysis of the RASSF1A promoter region in 45 primary breast cancers revealed that RASSF1A was frequently methylated in primary breast cancers (≥20% methylation in 53% of the patients), and prospective analysis in patients with locally advanced or recurrent breast cancer showed that the mean level of methylation of RASSF1A was significantly higher in patients who did not respond to docetaxel-based chemotherapy (30.6±8.5%) than patients with partial or complete response (20.1±11.2%, p=0.042). Finally, in vitro studies showed that RASSF1A had cooperative activity in suppression of cancer cell growth and proliferation by enhancing docetaxel-induced cell cycle arrest. Our results suggest that hypermethylated RASSF1A is an important modulating factor for the efficacy of docetaxel-based chemotherapy in breast cancer.

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