title: Thymidylate synthase and dihydropyrimidine dehydrogenase gene expression in breast cancer predicts 5-FU sensitivity by a histocultural drug sensitivity test.
abstract: Thymidylate synthase (TS), Dihydropyrimidine dehydrogenase (DPD) and Thymidine Phosphorylase (TP) gene expressions are reported to be predictive markers for 5-fluorouracil (5-FU) sensitivity in gastrointestinal cancer. However, in breast cancer, it is still controversial whether those molecular markers predict 5-FU sensitivity or not. One possible reason for the difficulty may be the histological heterogeneity in breast cancer specimens. In this study, TS, DPD and TP mRNA expression in 40 breast cancer tumors were semi-quantified separately in cancer cells (Ca), cancerous stroma (Str) and normal glands (Nor) using laser capture microdissection and real time RT-PCR (LCM+RT-PCR). The histoculture drug response assay (HDRA) for 5-FU sensitivity was performed for 22 tumors. TS and TP mRNA expressions were higher in Ca than Str, although DPD gene expression was lower in Ca than Str. The group of high TS and high DPD gene expression in Ca was resistant to 5-FU, and the group of low TS and low DPD gene expression in Ca was sensitive to 5-FU (P=0.048 chi-square test). TS and DPD mRNA expressions measured using LCM+RT-PCR might be useful predictive markers for 5-FU sensitivity in human breast cancer.
authors.affiliation: Breast Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima Bunkyo-ku, Tokyo, Japan. m-kakimoto.srg2@tmd.ac.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Kakimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uetake
authors.forename: Takayuki
authors.initials: T
authors.lastname: Osanai
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Shirota
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takagi
authors.forename: Emiko
authors.initials: E
authors.lastname: Takeshita
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Toriya
authors.forename: Kathleen
authors.initials: K
authors.lastname: Danenberg
authors.forename: Peter V
authors.initials: PV
authors.lastname: Danenberg
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sugihara
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001940:Breast / Q000201:enzymology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil