ANTICANCER RESEARCH 35: 5179-5184 (2015)

Review Predictive and Prognostic Value of the TauProtein in Breast Cancer

CLAIRE BONNEAU1, ZACHARY A. GURARD-LEVIN2, FABRICE ANDRE3, LAJOS PUSZTAI4 and ROMAN ROUZIER1,5

1Department of Breast and Gynaecological Surgery, Curie Institute, Versailles-St-Quentin-en-Yvelines University, Versailles, France; 2UMR3664: “Dynamic of the cell nucleus” Unit, National Center for scientific Research (CNRS), Curie Institute, Paris, France; 3UMR 981: “Predictive biomarkers and new molecular therapeutic strategies in cancer”, Integrated Research Cancer Institute in Villejuif, Paris, France; 4Yale Cancer Center Genetics and Genomics Program, Yale School of Medicine, New Haven, CT, U.S.A.; 5EA 7285: “Clinics risks and security in women's health and perinatal health”, Versailles-St-Quentin-en-Yvelines University, Versailles, France

Abstract. Background/Aim: Predictive markers for response Breast cancer is the most common malignant tumor in to are required in breast cancer. The Tau females (about 232,670 new cases of invasive breast cancer is a -associated protein variably are diagnosed per year in the United States for 2013). expressed in breast cancer. The objective of our study was to Women with localized breast cancer are usually first treated describe resistance induced by the tau protein, and its with locoregional surgery. When there are risk factors of predictive and prognostic value in breast cancer. Materials recurrence, they may be candidates for adjuvant systemic and Methods: Medline and PubMed databases were therapy, chemotherapy or endocrine therapy in order to searched in April 2015 for terms “tau protein”, “breast eradicate micrometastatic disease and prevent recurrence (1). cancer”, “chemotherapy sensitivity”, “biomarker” and The evaluation of risk of recurrence is clinical and “ resistance”. Results: In vitro, tau protein competes pathological: tumoral size, node involvement, with taxane for controlling microtubule dynamic and loss of lymphovascular invasion, nuclear grade, indicators of tau expression may render more vulnerable to proliferation (mitotic count, Ki-67 expression), expression of the effects of . High tau protein expression was hormonal receptors and amplification of human epidermal associated with better prognosis, even after adjustment for growth factor receptor-2 (HER2) (2). Women with locally grade, hormone receptor and human epidermal growth factor advanced breast cancer or with a tumor volume incompatible receptor-2 expression, nodal status. The predictive value of with conservative surgery usually undergo neoadjuvant the tau protein for sensitivity to taxane is discordant despite chemotherapy before surgery. Currently, chemotherapy is there being a trend for an association between low tau based on and taxanes, and is administered in expression and increased response rate. Conclusion: Tau more than half of all breast cancer cases. However, several protein expression is insufficient for identifying a subset of clinical trials also revealed that most of these patients fail to patients with carcinomas that may benefit more from benefit from chemotherapy because they present adverse chemotherapy. effects (3, 4). In this context, finding biomarkers that can predict sensitivity to chemotherapy is a priority. Tau protein was first described in Alzheimer's disease (5). Tau protein (50-64 kDa) is a product of a gene located on Correspondence to: Pr. Roman Rouzier, Institut Curie, Service de 17 (17q21). It belongs to the microtubule- Chirurgie, 35, rue Dailly 92210 Saint-Cloud, France. Tel: +33 associated protein (MAP) family. Microtubules are dynamic 0144324649/+33 0147111515, e-mail: [email protected] polymers composed of β- heterodimers and are Key Words: Microtubule-associated protein, tau protein, taxanes, essential components of the mitotic spindle and cytoskeleton. chemotherapy sensitivity, cancer treatment, breast cancer, review. Microtubules serve as scaffolds for signaling molecules,

0250-7005/2015 $2.00+.40 5179 ANTICANCER RESEARCH 35: 5179-5184 (2015) control cellular motility, cell shape, polarity, gene 17). The inverse correlation between tau protein and HER2 transcription and cell-cycle activity (6). Several bind expression is interesting as the gene for tau protein is to microtubules and either stabilize or de-stabilize their adjacent to HER2 on the 17q12 amplicon, yet rarely appears polymerization (6). Early preclinical and clinical reports to be co-expressed in HER2-positive tumors. Tau protein suggested that expression of tau protein modulates the expression did not correlate with tumor size, nodal status or sensitivity of malignant cells to chemotherapy, especially to patient age (11, 15-17). The association of Tau protein status taxanes, which are used in breast cancer (7-9). with menopausal status is not conclusive (15, 16). This review describes the mechanisms of drug resistance induced by the tau protein, and the prognostic and predictive Characterization of Tau Protein and values of the tau protein in breast cancer. Resistance to Taxanes

Materials and Methods Taxanes, or , belong to the spindle poison class. While taxanes bind to tubulin, on the microtubule’s Using the terms “tau protein”, “breast cancer”, “chemotherapy inner surface, microtubule depolymerization is inhibited (7). sensitivity”, “biomarker” and “taxane resistance”, a search was Microtubules, usually dynamically unstable, consequently carried-out on PubMed and Medline in April 2015. The references become stable structures. This disables spindle division and cited in the articles from this search were also evaluated for causes cell-cycle arrest in phase G /G of (18). The inclusion. Exclusion criteria were articles not published in English 1 2 or French, articles from before 1990, case reports, letters to the cytotoxic effect of paclitaxel also results from the induction editor, and expert opinions. The articles found were divided into of by the regulation of tumor-suppressor genes thematic groups: mechanisms of drug resistance induced by tau (p53, B-cell lymphoma-2 (BCL2) and BCL-2–associated X protein, and the prognostic and predictive values of tau protein in protein (BAX)). The efficiency of taxanes has been breast cancer. demonstrated in many types of cancers and they are widely used in breast cancer chemotherapy. Role and Regulation of Tau Protein Kinetic studies showed that tau protein binds to in Breast Epithelium microtubules differently depending on the presence or absence of paclitaxel (19). Tubulin polymerization assays Tau protein has the ability to combine with tubulin. It may revealed that microtubules pre-assembled in the presence of bind to the outer as well as the inner tubulin surface, at the tau protein bound less paclitaxel than microtubules same binding site as paclitaxel, and consequently it competes assembled without tau protein, and this reduced paclitaxel- with this drug. Tau protein is mainly expressed in the induced microtubule polymerization (10, 20). Small- neurons but is also found in normal breast epithelial cells interfering RNA experiments showed that down-regulation (10). Its role in the cancer process is likely due to the of tau protein increased the sensitivity of breast cancer cells importance of microtubules in mitosis. In a study of 1,942 to paclitaxel and docetaxel, minimally increased that to patients with breast cancer, in 43% of patients, tau protein but not that to , in vitro. Conversely, expression was greater than that of normal breast epithelium induction of tau protein expression with retinoic acid (i.e. tau protein-positive) (11). increased breast cancer cell resistance to paclitaxel, Tau protein contains an imperfect estrogen-response suggesting a protective effect (9). These data support that the element upstream of its promoter and is an estrogen-induced loss of tau protein expression may render microtubules protein expressed by cultured neurons and breast cancer cell hyper-vulnerable to paclitaxel, or that tau protein, at least lines (10, 12, 13). All studies have found that tau protein partially, protects microtubules from paclitaxel binding. expression correlates closely with estrogen receptor (ER) expression in breast cancer. Tau protein expression was Prognostic Value of Tau Protein Expression significantly more frequent among patients with ER-positive cancer, 57-65% of these tumors were tau protein-positive A prognostic factor is a clinical or biological characteristic compared with 15-30% of those with ER-negative tumors that provides information on the likely outcome of cancer in (11, 14-17). Tau protein positivity was also correlated with an untreated individual. This is helpful for identifying positive progesterone receptor (PR) status, lower histological patients with cancer who are at high risk of metastatic grade and lack of human epidermal growth factor receptor 2 relapse and who are, therefore, potential candidates for (HER2): 63% of PR-positive tumors were tau-positive adjuvant systemic treatments. compared to 36% of PR-negative tumors; 60% of low-grade The first study to assess the prognostic value of tau tumors were tau-positive compared to 30% of high-grade protein mRNA expression in 209 patients with node- tumors; and 2.4% of HER2+ tumors compared were tau- negative, ER-positive disease who received no adjuvant positive compared to 20% of HER2-negative tumors (11, 15- systemic therapy showed a borderline non-significant

5180 Bonneau et al: Tau Protein in Breast Cancer (Review)

Table I. Predictive values for response to taxanes and prognostic values of Tau in patients with breast cancer.

Study N Type of Method of Tau End Prognostic Predictive value for cancer evaluation point value response to taxanes

Rouzier et al. (10) 122 Breast cancer stage I-III, Tau protein (IHC) pCR - Yes neoadjuvant therapy Andre et al. (14) 209 Breast cancer, ER+, N−, Tau mRNA RFS No - no systemic adjuvant therapy OS 82 Breast cancer, ER+, stage I-III, Tau mRNA pCR - Yes neoadjuvant therapy Rody et al. (25) 50 Breast cancer stage IIA-IIIB Tau mRNA pCR - No neoadjuvant therapy Tanaka et al. (22) 35 Metastatic breast cancer Tau protein (IHC) TTP - Yes Pentheroudakis et al. (16) 274 Breast cancer stage I-IIB, Tau mRNA RFS Yes No adjuvant chemotherapy OS (HeCOG trial HE 10/97) Pusztai et al. (11) 1942 Breast cancer, stage I-IIIA, Tau protein (IHC) RFS Yes for ER+ No adjuvant chemotherapy OS No for ER− (NASPB-B28 trial) Shao et al. (17) 54 Locally advanced or metastatic Tau protein (IHC) ORR Yes Yes breast cancer RFS OS Baquero et al. (15) 651 Breast cancer, stage I-III Tau protein (QIF) OS Yes for ER− - (Yale University breast TTP No for ER+ cancer cohort) 140 Metastatic breast cancer Tau protein (QIF) OS Yes No (TAX 307 cohort) TTP Wang et al. (23) 113 Breast cancer, stage I-III, Tau protein (IHC) pCR - Yes neoadjuvant chemotherapy

IHC, immunohistochemistry; QIF, quantitative immunofluorescence; pCR, pathological complete response; ER+/−, estrogen receptor-positive/- negative; N, node negative; RFS, recurrence-free survival; OS, overall survival; ORR, overall response rate; TTP, time to progression.

association between higher tau protein mRNA expression protein expression was associated with improved survival and better prognosis (14). Another study on 274 patients compared to those with low expression (p=0.006) (15). with high-risk early breast cancer from the HeCOG trial When stratified by ER status, tau protein had prognostic HE10/97 conducted univariate and multivariate Cox value in patients with ER-negative but not in ER-positive regression analysis. The multivariate analysis, including patients. In the ER-negative/high tau protein expressers menopausal status; tumor grade; tumor size; number of (n=35), they observed improved survival compared with low positive lymph nodes; treatment group; and ER, PR, and tau expressers (p=0.006). Similarly, patients stratified by HER2 mRNA expression, revealed that only mRNA expression and status showed improved survival for those with high tau the number of involved axillary nodes remained significant protein/HER2-positive expression compared with those with independent predictors of overall survival (OS), while tau low tau protein/HER2-positive expression (p=0.007), mRNA expression, number of positive nodes and tumor although the coexpression of tau and HER2 was a rare grade, independently predicted disease-free survival (DFS) event. (16). Positive tau mRNA expression was associated with a High tau protein expression was significantly associated decreased risk of death with an hazard ratio (HR) of 0.46 with longer OS, with an HR of 0.42 (p=0.02) in a study (95% confidence interval (CI)=0.25-0.85; p=0.01) and a including 54 patients with advanced or metastatic breast decreased risk of relapse with an HR of 0.53 (95% CI=0.32- cancer (17). The estimated median OS time was 57.5 months 0.89; p=0.02). In the ancillary study of the NSABP-B28 (95% CI=36.2-78.8 months) for patients with high tau trial, among the patients with ER-positive disease (n=1287), protein expression and 30.4 months (95% CI=26.7-34.1 patients with tau protein-positive cancer (n=736) had better months) for those with low tau protein expression. Similarly, DFS and OS compared to those with tau protein-negative when the TAX 307S cohort (140 patients with metastatic tumors (11). Among patients with ER-negative disease breast cancer) was stratified by tau protein expression, tau (n=655), tau protein expression had no prognostic value. In protein had a prognostic value, with improved median time the Yale university cohort including 651 patients, high tau to PFS for high tau protein-expression cases (n=35)

5181 ANTICANCER RESEARCH 35: 5179-5184 (2015) compared to low-expression cases (n=73; 33.0 vs. 23.4 a candidate novel marker for paclitaxel response in the months) and a mean time to progression of 31.2 months highlights of the tenth St. Gallen international conference on (p=0.010), suggesting that this marker maintains prognostic primary therapy for early breast cancer (21). value in patients with metastatic disease (15). Similar results were reported on a small cohort of 35 patients treated with paclitaxel for metastatic breast cancer Predictive Value of the Tau Protein (22): 60% of patients with tau protein-negative status showed favorable response (complete or partial response according to Sensitivity to chemotherapy. A predictive marker is a RECIST criteria) to paclitaxel administration compared to characteristic that provides information on the likely benefit 15% of patients with tau-positive status. The OR for favorable from treatment. It can be used to identify sub-populations of response in patients with tau protein-negative tumors was 8.5 patients who are most likely to benefit from a given therapy. (95% CI=1.7-42.3; p=0.01). In addition, the duration of According to in vitro studies, tau protein was a candidate response was 10.7±5.7 months for the tau protein-negative predictive marker for response to chemotherapy. group and 6.0±2.0 months for the positive group, and time to In 2005, Rouzier et al. conducted the first study involving disease progression was 9.4±6.6 months and 6.0±3.7 months, tau protein in breast cancer (10). They included 122 patients respectively. Two other studies, including 54 patients with with stage I-III breast cancer treated with neoadjuvant advanced or metastatic breast cancer receiving paclitaxel therapy. Indeed, administration of chemotherapy before chemotherapy and 113 patients with breast cancer patients surgery provides an opportunity to directly measure tumor receiving neoadjuvant chemotherapy, showed that tau protein response and identify molecular predictors. Several large expression was significantly associated with a lower overall retrospective studies have demonstrated that complete response rate and pCR respectively, in univariate and eradication of all invasive cancer from the breast and axillary multivariate analysis (Table I) (17, 23). lymph nodes after preoperative chemotherapy, i.e. Conversely, in the ancillary study of the HeCOG trial pathological complete response (pCR), is associated with HE10/97 including 274 patients with high-risk early breast excellent cancer-free survival (6, 7). Therefore, molecular cancer treated with paclitaxel, the predictive role of tau predictors of pCR should help identify individuals who are protein for response to chemotherapy was not confirmed most likely to benefit from a particular therapy. They first (16). The objective of this study was to study the predictive used gene-expression profiling (U133A chip) to discover significance and correlations of transcriptional profiling of genes associated with extreme chemotherapy sensitivity. The the genes for ER, PR and tau protein in breast cancer. In most significantly differentially expressed gene between multivariate models, they found that neither tau mRNA nor cases with pCR and those with residual cancer was ER mRNA expression status were predictive for benefit from microtubule-associated tau protein (lower tau mRNA adjuvant treatment with paclitaxel for either DFS or OS. expression in tumors from patients that achieved pCR) (10). Restricting analysis to ER-positive tumors, tau mRNA They then used tissue arrays from the same patients for expression status remained non-predictive for benefit from validation by immunohistochemistry. Tau-negative status was adjuvant treatment with paclitaxel. As the majority of this associated with an odds ratio (OR) for pCR of 3.7 (95% cohort received endocrine therapy after chemotherapy, it is CI=1.6-8.6; p=0.0013). In multivariate analysis (including possible that any predictive significance of low tau mRNA patient age; tumor size; histological type and grade; and ER, expression for taxane benefit was cancelled out by resistance PR, HER2 and tau protein status), nuclear grade, age less to hormonal therapy, resulting in no detectable differences in than 50 years and tau protein-negative status were outcome. Moreover the authors point-out that in the entire independent predictors of pCR (Table I). HE10/97 trial, the addition of taxanes reduced the hazard of In a second study of 82 patients with ER-positive tumors death only in patients with ER-negative disease (24). Given who received neoadjuvant chemotherapy including the correlation of ER and tau gene activity, it is possible that paclitaxel, the pCR rate was 19% in the lowest tertile of tau patients with ER-negative disease who benefit from taxanes protein expression, 3% in the median tertile, and 0% in the are mostly tau protein-negative. This effect may have been highest tertile (14). Multivariate logistic regression analysis lost in their cohort as the number of patients evaluated was including age, tumor size, nodal status, ER expression and reduced to less than half due to limitations in tissue tau protein indicated that tau protein remained a significant availability. Another study of 50 patients treated by independent predictor of pCR. High tau expression was neoadjuvant chemotherapy for breast cancer failed to find associated with a decreased OR for pCR of 0.14, (95% any predictive value of tau protein for response to taxane CI=0.03-0.59; p=0.008) (Table I). These results corroborated (25). However, the population was poor and they used the previous observation that low tau protein expression in docetaxel rather than paclitaxel, which is more commonly ER-positive breast cancer was associated with paclitaxel used in other studies. This limits comparability with other sensitivity (10). Thus, tau protein expression was adopted as studies.

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In this context of contradictory results about the predictive HER2-positive tumors, and probably to a distinct genetic value of tau protein, an ancillary study on the NASBP-B28 program. In addition, tau protein interactions with estrogen trial was conducted including 1,942 patients with breast and tamoxifen may be a bias in the interpretation of studies cancer treated with adjuvant chemotherapy (11). Although previously presented. that study had the greatest number of patient assessed for tau To enhance our comprehension of tau protein in breast protein in breast cancer, there was no significant interaction cancer, further studies should evaluate the importance of its between tau protein expression and benefit from paclitaxel isoforms and the effect of phosphorylation of tau protein as in the total population, nor by ER status. This was confirmed the microarray probe sets and the antibody used were on the TAX 307 cohort with 140 patients with metastatic directed against shared domains of the isoforms and were not breast cancer (15). No significant interaction between tau sensitive to phosphorylation status. They should also assess protein expression and benefit from docetaxel was observed the prognostic and predictive value of tau protein in subset and response rates to docetaxel therapy as a function of tau of cohort such as by ER status. protein expression did not differ when partitioned by ER High tau protein expression is associated with a good status, adjuvant endocrine therapy, or taxane treatment arm. prognosis in breast cancer. The predictive value of tau protein for response to chemotherapy remains uncertain, mostly due Sensitivity to endocrine therapy. Only one study has to interaction with ER status. In fact, tau protein expression is examined the predictive value of tau protein for sensitivity not sufficient for selecting patients for chemotherapy. to endocrine therapy in breast cancer (14). It included 267 ER-positive tumors from patients who received 5 years of Conflicts of Interest adjuvant tamoxifen therapy. Multivariate Cox regression analysis including age, tumor size, nodal status, ER The Authors declare no conflicts of interest with regard to this study. expression, and tau protein expression indicated that tau protein was a significant independent predictor of outcome. 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