title: Promoter methylation of RASSF1A modulates the effect of the microtubule-targeting             agent docetaxel in breast cancer.
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.
authors.affiliation: Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Gil
authors.forename: Uk Hyun
authors.initials: UH
authors.lastname: Jo
authors.forename: Hoiseon
authors.initials: H
authors.lastname: Jeong
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Whang
authors.forename: Ok Hee
authors.initials: OH
authors.lastname: Woo
authors.forename: Kyu Ran
authors.initials: KR
authors.lastname: Cho
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
authors.forename: Aeree
authors.initials: A
authors.lastname: Kim
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Lee
authors.forename: Insong
authors.initials: I
authors.lastname: Koh
authors.forename: Yeul Hong
authors.initials: YH
authors.lastname: Kim
authors.forename: Kyong Hwa
authors.initials: KH
authors.lastname: Park
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D000077143:Docetaxel; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016015:Logistic Models; D015999:Multivariate Analysis; D018299:Neoplasms, Ductal, Lobular, and Medullary / Q000188:drug therapy* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C411762:RASSF1 protein, human; D043823:Taxoids; D050257:Tubulin Modulators; D025521:Tumor Suppressor Proteins; D000077143:Docetaxel