Journal article
Novel mutations involving βI-, βIIA-, or βIVB-tubulin isotypes with functional resemblance to βIII-tubulin in breast cancer
Protoplasma, v 254(3), pp 1163-1173
May 2017
PMID: 27943021
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Tubulin is the target for very widely used anti-tumor drugs, including Vinca alkaloids, taxanes, and epothilones, which are an important component of chemotherapy in breast cancer and other malignancies. Paclitaxel and other tubulin-targeting drugs bind to the β subunit of tubulin, which is a heterodimer of α and β subunits. β-Tubulin exists in the form of multiple isotypes, which are differentially expressed in normal and neoplastic cells and differ in their ability to bind to drugs. Among them, the βIII isotype is overexpressed in many aggressive and metastatic cancers and may serve as a prognostic marker in certain types of cancer. The underpinning mechanisms accounting for the overexpression of this isotype in cancer cells are unclear. To better understand the role of β-tubulin isotypes in cancer, we analyzed over 1000 clones from 90 breast cancer patients, sequencing their β-tubulin isotypes, in search of novel mutations. We have elucidated two putative emerging molecular subgroups of invasive breast cancer, each of which involve mutations in the βI-, βIIA-, or βIVB isotypes of tubulin that increase their structural, and possibly functional, resemblance to the βIII isotype. A unifying feature of the first of the two subgroups is the mutation of the highly reactive C239 residue of βI- or βIVB-tubulin to L239, R239, Y239, or P239, culminating in probable conversion of these isotypes from ROS-sensitive to ROS-resistant species. In the second subgroup, βI, βIIA, and βIVB have up to seven mutations to the corresponding residues in βIII-tubulin. Given that βIII-tubulin has emerged as a pro-survival factor, overexpression of this isotype may confer survival advantages to certain cancer cell types. In this mini-review, we bring attention to a novel mechanism by which cancer cells may undergo adaptive mutational changes involving alternate β-tubulin isotypes to make them acquire some of the pro-survival properties of βIII-tubulin. These "hybrid" tubulins, combining the sequences and/or properties of two wild-type tubulins (βIII and either βI, βIIA, or βIVB), are novel isotypes expressed solely in cancer cells and may contribute to the molecular understanding and stratification of invasive breast cancer and provide novel molecular targets for rational drug development.
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Details
- Title
- Novel mutations involving βI-, βIIA-, or βIVB-tubulin isotypes with functional resemblance to βIII-tubulin in breast cancer
- Creators
- Weiwei Wang - University of AlbertaHangxiao Zhang - Beijing Institute of GenomicsXumin Wang - Beijing Institute of GenomicsJordan Patterson - University of AlbertaPhilip Winter - University of AlbertaKathryn Graham - University of AlbertaSunita Ghosh - University of AlbertaJohn C Lee - The University of Texas Health Science Center at San AntonioChristos D Katsetos - Drexel UniversityJohn R Mackey - University of AlbertaJack A Tuszynski - University of AlbertaGane Ka-Shu Wong - University of AlbertaRichard F Ludueña - The University of Texas Health Science Center at San Antonio
- Publication Details
- Protoplasma, v 254(3), pp 1163-1173
- Publisher
- Springer Nature
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:000399037400004
- Scopus ID
- 2-s2.0-85003936042
- Other Identifier
- 991019353620304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Plant Sciences