title: Novel mutations involving βI-, βIIA-, or βIVB-tubulin isotypes with functional resemblance to βIII-tubulin in breast cancer.
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.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Beijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Hangxiao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Xumin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Patterson
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Winter
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Graham
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
authors.forename: Sunita
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, 19134, USA.|Department of Pathology and Laboratory Medicine, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, 19134, USA.
authors.forename: Christos D
authors.initials: CD
authors.lastname: Katsetos
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada.|Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2E9, Canada.|BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China.
authors.forename: Gane Ka-Shu
authors.initials: GK
authors.lastname: Wong
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. Luduena@uthscsa.edu.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ludueña
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002645:Chickens; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D012474:Salmon; D017422:Sequence Analysis, DNA / Q000662:veterinary; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D000970:Antineoplastic Agents; D020033:Protein Isoforms; D014404:Tubulin; D017239:Paclitaxel
keywords: Anti-tumor drugs; Breast cancer; Cancer-associated mutations; Microtubule dynamics; Tubulin isotypes; βIII-tubulin