Cytoskeleton and paclitaxel sensitivity in breast cancer: The role of β-tubulins

The antineoplastic effect of paclitaxel is mainly related to its ability to bind the β subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. The relevance of the Class I β-tubulin characteristics have also been confirmed in the clinical setting where mutations of paclitaxel-binding site of β-tubulin Class I have been related to paclitaxel resistance in non small cell lung and ovarian cancers. In the present study, we verified the hypothesis of a relationship between molecular alterations of β-tubulin Class I and paclitaxel sensitivity in a panel of breast cell lines with different drug IC₅₀. The Class I β-tubulin gene cDNA has been sequenced detecting heterozygous missense mutations (exon 1 and 4) only in MCF-7 and SK-BR-3 lines. Furthermore, the expression (at both mRNA and protein level) of the different isotypes have been analyzed demonstrating an association between low cell sensitivity to paclitaxel and Class III β-tubulin expression increasing. Antisense oligonucleotide (ODN) experiments confirmed that the inhibition of Class III β-tubulin could at least partially increase paclitaxel-chemosensitivity. The hypothesis of a relationship between β-tubulin tumor expression and paclitaxel clinical response has been finally verified in a series of 92 advanced breast cancer patients treated with a first line paclitaxel-based chemotherapy. Thirty-five percent (95% CI: 45-31) of patients with high Class III β-tubulin expression showed a disease progression vs. only 7% of patients with low expression (35% vs. 7%, p <0.002). Our study suggests that Class III β-tubulin tumor expression could be considered a predictive biomarker of paclitaxel-clinical resistance for breast cancer patients.