Tubulin detyrosination is a frequent occurrence in breast cancers of poor prognosis

Tubulin, the dimeric subunit of microtubules, is a major cell protein that is: centrally involved in cell division, Tubulin is subject to specific enz ymatic posttranslational modifications including cyclic tyrosine removal an d addition at the COOK terminus of the cr-subunit. Tubulin is normally exte nsively tyrosinated in cycling cells. However, we have previously shown tha t detyrosinated tubulin accumulates in cancer cells during tumor progressio n in nude mice. Tubulin detyrosination, resulting from suppression of tubul in tyrosine ligase and the resulting unbalanced activity of tubulin-carboxy peptidase, apparently represents a strong selective advantage for cancer ce lls. We have now analyzed the occurrence and significance of tubulin detyro sination in human breast tumors. We studied a total of 134 breast cancer tu mors from patients with or without known complications over a follow-up per iod of 31 +/- 10 months. The mean age of the patients at the time of diagno sis was 57 years. For each patient, detailed data concerning the histology and extension of the tumor were available. Tumor cells containing detyrosin ated tubulin were visualized by immunohistochemical staining of paraffin-em bedded tissue sections. Cancer cells with detyrosinated tubulin were observed in 53% of the tumors and were predominant in 19.4% of the turners. Tubulin detyrosination correl ated to a high degree of significance (P < 0.001) with a high Scarf;Bloom-R ichardson (SBR) grade, a known marker of tumor aggressiveness. Among SBR gr ade 1 tumors, 3.8% were strongly positive for tubulin detyrosination compar ed with 65.4% of the SBR grade 3 tumors. The SBR component showing the stro ngest correlation with tubulin detyrosination was the mitotic score. In the entire patient population, neither the SBR grade nor the detyrosination in dex had significant prognostic value (P = 0.11, P = 0.27, respectively), wh ereas a combined index was significantly correlated with the clinical outco me (P = 0.02), A preliminary subgroup analysis indicated that tubulin detyr osination may define high- and low- risk groups in breast cancer tumors wit h an SBR grade of 2. Our study shows that tubulin detyrosination is a frequ ent occurrence in breast cancer, easy to detect, and linked to tumor aggres siveness.