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 alpha-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.