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 paclitaxelcontaining 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 ؋ 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 ϭ 0.0013). In multivariate analysis, nuclear grade (P < 0.01), age <50 (P ϭ 0.03), and taunegative status (P ϭ 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 paclitaxelinduced 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. adjuvant therapy ͉ drug resistance

Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

“…Indeed, Rouzier et al reported that MAP-Tau gene expression was inversely associated with pathologic complete response (pCR) of breast carcinomas to neoadjuvant paclitaxel-based chemotherapy. Among 82 patients treated with T-FAC induction regimen, pCR occurred in 44% of MAPTau mRNA-negative tumors, but only in 17% of MAP-Tau mRNA-positive ones (P = 0.04) [34].…”

Developing gene expression signatures of pathway deregulation in tumors

“…In addition to technical issues, such as lack of a standard technology platform and difficulties surrounding the collection of clinical samples, the myriad cellular processes affected by cytotoxic chemotherapies may hinder the identification of practical and robust gene expression predictors of response to these agents. One exception may be the recent finding by microarray that low mRNA expression of the microtubule-associated protein Tau is predictive of improved response to paclitaxel (6).…”

Prediction of pathologic complete response to sequential paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide therapy using a 70-gene classifier for breast cancers

“…Because sequential taxane and anthracycline-containing regimens are used most widely in the neoadjuvant setting, many attempts have been made to develop predictors for pCR to these regimens. Negative estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) amplification, tau, and others [3][4][5][6] reportedly are associated significantly with a high pCR rate, but their diagnostic accuracy is not good enough to make their use in practice feasible, thus necessitating the development of a more accurate and clinically useful predictor for pCR.…”