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 journalArticle

120 Citations (Scopus)

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

Fingerprint

Tubulin
Paclitaxel
Cytoskeleton
Breast Neoplasms
MHC Class I Genes
Antisense Oligonucleotides
Missense Mutation
Non-Small Cell Lung Carcinoma
Antineoplastic Agents
Ovarian Neoplasms
Inhibitory Concentration 50
Disease Progression
Exons
Neoplasms
Breast
Complementary DNA
Biomarkers
Binding Sites
Apoptosis
Drug Therapy

Keywords

  • Cell lines
  • Drug sensitivity
  • Taxanes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cytoskeleton and paclitaxel sensitivity in breast cancer : The role of β-tubulins. / Tommasi, Stefania; Mangia, Anita; Lacalamita, Rosanna; Bellizzi, Antonia; Fedele, Vita; Chiriatti, Annalisa; Thomssen, Christopher; Kendzierski, Nancy; Latorre, Agnese; Lorusso, Vito; Schittulli, Francesco; Zito, Francesco; Kavallaris, Maria; Paradiso, Angelo.

In: International Journal of Cancer, Vol. 120, No. 10, 15.05.2007, p. 2078-2085.

Research output: Contribution to journalArticle

Tommasi, S, Mangia, A, Lacalamita, R, Bellizzi, A, Fedele, V, Chiriatti, A, Thomssen, C, Kendzierski, N, Latorre, A, Lorusso, V, Schittulli, F, Zito, F, Kavallaris, M & Paradiso, A 2007, 'Cytoskeleton and paclitaxel sensitivity in breast cancer: The role of β-tubulins', International Journal of Cancer, vol. 120, no. 10, pp. 2078-2085. https://doi.org/10.1002/ijc.22557
Tommasi, Stefania ; Mangia, Anita ; Lacalamita, Rosanna ; Bellizzi, Antonia ; Fedele, Vita ; Chiriatti, Annalisa ; Thomssen, Christopher ; Kendzierski, Nancy ; Latorre, Agnese ; Lorusso, Vito ; Schittulli, Francesco ; Zito, Francesco ; Kavallaris, Maria ; Paradiso, Angelo. / Cytoskeleton and paclitaxel sensitivity in breast cancer : The role of β-tubulins. In: International Journal of Cancer. 2007 ; Vol. 120, No. 10. pp. 2078-2085.
@article{e410a50c0854438188109afcfa8c318b,
title = "Cytoskeleton and paclitaxel sensitivity in breast cancer: The role of β-tubulins",
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.",
keywords = "Cell lines, Drug sensitivity, Taxanes",
author = "Stefania Tommasi and Anita Mangia and Rosanna Lacalamita and Antonia Bellizzi and Vita Fedele and Annalisa Chiriatti and Christopher Thomssen and Nancy Kendzierski and Agnese Latorre and Vito Lorusso and Francesco Schittulli and Francesco Zito and Maria Kavallaris and Angelo Paradiso",
year = "2007",
month = "5",
day = "15",
doi = "10.1002/ijc.22557",
language = "English",
volume = "120",
pages = "2078--2085",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "10",

}

TY - JOUR

T1 - Cytoskeleton and paclitaxel sensitivity in breast cancer

T2 - The role of β-tubulins

AU - Tommasi, Stefania

AU - Mangia, Anita

AU - Lacalamita, Rosanna

AU - Bellizzi, Antonia

AU - Fedele, Vita

AU - Chiriatti, Annalisa

AU - Thomssen, Christopher

AU - Kendzierski, Nancy

AU - Latorre, Agnese

AU - Lorusso, Vito

AU - Schittulli, Francesco

AU - Zito, Francesco

AU - Kavallaris, Maria

AU - Paradiso, Angelo

PY - 2007/5/15

Y1 - 2007/5/15

N2 - 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.

AB - 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.

KW - Cell lines

KW - Drug sensitivity

KW - Taxanes

UR - http://www.scopus.com/inward/record.url?scp=34147187180&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34147187180&partnerID=8YFLogxK

U2 - 10.1002/ijc.22557

DO - 10.1002/ijc.22557

M3 - Article

C2 - 17285590

AN - SCOPUS:34147187180

VL - 120

SP - 2078

EP - 2085

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 10

ER -