title: Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer.
abstract: Breast cancers show variable sensitivity to paclitaxel. There is no diagnostic test to identify tumors that are sensitive to this drug. We used U133A chips to identify genes that are associated with pathologic complete response (pCR) to preoperative paclitaxel-containing chemotherapy in stage I-III breast cancer (n = 82). Tau was the most differentially expressed gene. Tumors with pCR had significantly lower (P < 0.3 x 10(-5)) mRNA expression. Tissue arrays from 122 independent but similarly treated patients were used for validation by immunohistochemistry. Seventy-four percent of pCR cases were tau protein negative; the odds ratio for pCR was 3.7 (95% confidence interval, 1.6-8.6; P = 0.0013). In multivariate analysis, nuclear grade (P < 0.01), age <50 (P = 0.03), and tau-negative status (P = 0.04) were independent predictors of pCR. Small interfering RNA experiments were performed to examine whether down-regulation of tau increases sensitivity to chemotherapy in vitro. Down-regulation of tau increased sensitivity of breast cancer cells to paclitaxel but not to epirubicin. Tubulin polymerization assay was used to assess whether tau modulates binding of paclitaxel to tubulin. Preincubation of tubulin with tau resulted in decreased paclitaxel binding and reduced paclitaxel-induced microtubule polymerization. These data suggest that low tau expression renders microtubules more vulnerable to paclitaxel and makes breast cancer cells hypersensitive to this drug. Low tau expression may be used as a marker to select patients for paclitaxel therapy. Inhibition of tau function might be exploited as a therapeutic strategy to increase sensitivity to paclitaxel.
authors.affiliation: Department of Breast Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Rouzier
authors.forename: Radhika
authors.initials: R
authors.lastname: Rajan
authors.forename: Peter
authors.initials: P
authors.lastname: Wagner
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.forename: David L
authors.initials: DL
authors.lastname: Gold
authors.forename: James
authors.initials: J
authors.lastname: Stec
authors.forename: Mark
authors.initials: M
authors.lastname: Ayers
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Peter
authors.initials: P
authors.lastname: Zhang
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchholz
authors.forename: Henry
authors.initials: H
authors.lastname: Kuerer
authors.forename: Marjorie
authors.initials: M
authors.lastname: Green
authors.forename: Banu
authors.initials: B
authors.lastname: Arun
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: W Fraser
authors.initials: WF
authors.lastname: Symmans
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003520:Cyclophosphamide / Q000494:pharmacology; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D016875:tau Proteins; D015251:Epirubicin; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil