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

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)611-620
Number of pages10
JournalInternational Journal of Oncology
Volume41
Issue number2
DOIs
Publication statusPublished - 2012 Aug 1

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docetaxel
Microtubules
Methylation
Breast Neoplasms
Carcinoma, Intraductal, Noninfiltrating
Drug Therapy
Cell Line

Keywords

  • Breast cancer
  • Cyclin B1
  • Docetaxel
  • Methylation
  • RASSF1A

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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.

In: International Journal of Oncology, Vol. 41, No. 2, 01.08.2012, p. 611-620.

Research output: Contribution to journalArticle

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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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AU - Koh, Insong

AU - Kim, Yeul Hong

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