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Protoplasma. 2017 May;254(3):1163-1173. doi: 10.1007/s00709-016-1060-1. Epub 2016 Dec 9.

Novel mutations involving βI-, βIIA-, or βIVB-tubulin isotypes with functional resemblance to βIII-tubulin in breast cancer.

Author information

1
Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada.
2
Beijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing, 100101, China.
3
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
4
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
5
Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, 19134, USA.
6
Department of Pathology and Laboratory Medicine, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, 19134, USA.
7
Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2E9, Canada.
8
BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China.
9
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. Luduena@uthscsa.edu.

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.

KEYWORDS:

Anti-tumor drugs; Breast cancer; Cancer-associated mutations; Microtubule dynamics; Tubulin isotypes; βIII-tubulin

PMID:
27943021
DOI:
10.1007/s00709-016-1060-1
[Indexed for MEDLINE]

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