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Predictive and Prognostic Value of the Tauprotein in Breast Cancer

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Predictive and Prognostic Value of the Tauprotein in Breast Cancer 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 chemotherapy are required in breast cancer. The Tau females (about 232,670 new cases of invasive breast cancer protein is a microtubule-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 drug 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 “taxane 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 microtubules more vulnerable to proliferation (mitotic count, Ki-67 expression), expression of the effects of taxanes. 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 anthracyclines 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 chromosome 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-tubulin 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 proteins 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, paclitaxel or docetaxel, 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 mitosis (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 apoptosis 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 vinorelbine but not that to epirubicin, 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
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