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

Stefania Tommasi, Anita Mangia, Rosanna Lacalamita, Antonia Bellizzi, Vita Fedele, Annalisa Chiriatti, Christopher Thomssen, Nancy Kendzierski, Agnese Latorre, Vito Lorusso, Francesco Schittulli, Francesco Zito, Maria Kavallaris, Angelo Paradiso

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2078-2085
Number of pages8
JournalInternational Journal of Cancer
Volume120
Issue number10
DOIs
Publication statusPublished - May 15 2007

Keywords

  • Cell lines
  • Drug sensitivity
  • Taxanes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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