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 language | English |
|---|---|
| Pages (from-to) | 2078-2085 |
| Number of pages | 8 |
| Journal | International Journal of Cancer |
| Volume | 120 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - May 15 2007 |
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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 journal › Article
}
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 -