Cytoskeleton and paclitaxel sensitivity in breast cancer: the role of beta-tubulins.
The antineoplastic effect of paclitaxel is mainly related to its ability to bind the beta subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. The relevance of the Class I beta-tubulin characteristics have also been confirmed in the clinical setting where mutations of paclitaxel-binding site of beta-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 beta-tubulin Class I and paclitaxel sensitivity in a panel of breast cell lines with different drug IC(50). The Class I beta-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 beta-tubulin expression increasing. Antisense oligonucleotide (ODN) experiments confirmed that the inhibition of Class III beta-tubulin could at least partially increase paclitaxel-chemosensitivity. The hypothesis of a relationship between beta-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 beta-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 beta-tubulin tumor expression could be considered a predictive biomarker of paclitaxel-clinical resistance for breast cancer patients.
Tommasi
Stefania
S
Clinical Experimental Oncology Laboratory, National Cancer Institute, via Amendola 209, 70126 Bari, Italy.
Mangia
Anita
A
Lacalamita
Rosanna
R
Bellizzi
Antonia
A
Fedele
Vita
V
Chiriatti
Annalisa
A
Thomssen
Christopher
C
Kendzierski
Nancy
N
Latorre
Agnese
A
Lorusso
Vito
V
Schittulli
Francesco
F
Zito
Francesco
F
Kavallaris
Maria
M
Paradiso
Angelo
A
D000595:Amino Acid Sequence; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D017239:Paclitaxel / Q000494:pharmacology*; D020033:Protein Isoforms; D012189:Retrospective Studies; D014404:Tubulin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000972:Antineoplastic Agents, Phytogenic; D020033:Protein Isoforms; D014404:Tubulin; D017239:Paclitaxel