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Tubulin Detyrosination Is a Frequent Occurrence in Breast Cancers of Poor Prognosis¹

Laboratoire du Cytosquelette, Institut National de la Santé et de la Recherche Médicale (INSERM) U366, Département de Biologie Molèeculaire et Structurale, Commissariat á l’Energie Atomique, 38054 Grenoble Cedex 9, France [A. M., L. L., D. J.]; Département d’Anatomie et de Cytologie Pathologiques, Centre Léon Bérard, 69373 Lyon, France [I. T., N. P., C. D., A. B.]; Clinique Belledonne, 38400 Saint Martin d’Hèeres, France [M. H. P., R. P.]; Gesellschaft für Biotechnologische Forschung mbH, 38092 Braunschweig, Germany [J. W.]; and Institut de Biologie Structurale J. P. Ebel (Commissariat á l’Energie Atomique-Centre National de la Recherche Scientifique), 38027 Grenoble Cedex 1, France [R. L. M.]

Tubulin, the dimeric subunit of microtubules, is a major cell protein that is centrally involved in cell division. Tubulin is subject to specific enzymatic posttranslational modifications including cyclic tyrosine removal and addition at the COOH terminus of the -subunit. Tubulin is normally extensively tyrosinated in cycling cells. However, we have previously shown that detyrosinated tubulin accumulates in cancer cells during tumor progression in nude mice. Tubulin detyrosination, resulting from suppression of tubulin tyrosine ligase and the resulting unbalanced activity of tubulin-carboxypeptidase, apparently represents a strong selective advantage for cancer cells. We have now analyzed the occurrence and significance of tubulin detyrosination in human breast tumors. We studied a total of 134 breast cancer tumors from patients with or without known complications over a follow-up period of 31 ± 10 months. The mean age of the patients at the time of diagnosis was 57 years. For each patient, detailed data concerning the histology and extension of the tumor were available. Tumor cells containing detyrosinated tubulin were visualized by immunohistochemical staining of paraffin-embedded tissue sections.

Cancer cells with detyrosinated tubulin were observed in 53% of the tumors and were predominant in 19.4% of the tumors. Tubulin detyrosination correlated to a high degree of significance (P < 0.001) with a high Scarf-Bloom-Richardson (SBR) grade, a known marker of tumor aggressiveness. Among SBR grade 1 tumors, 3.8% were strongly positive for tubulin detyrosination compared with 65.4% of the SBR grade 3 tumors. The SBR component showing the strongest correlation with tubulin detyrosination was the mitotic score. In the entire patient population, neither the SBR grade nor the detyrosination index had significant prognostic value (P = 0.11, P = 0.27, respectively), whereas a combined index was significantly correlated with the clinical outcome (P = 0.02). A preliminary subgroup analysis indicated that tubulin detyrosination may define high- and low- risk groups in breast cancer tumors with an SBR grade of 2. Our study shows that tubulin detyrosination is a frequent occurrence in breast cancer, easy to detect, and linked to tumor aggressiveness.

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