Int J Biol Sci 2022; 18(1):1-14. doi:10.7150/ijbs.64167 This issue

Research Paper

Dysregulation of Transglutaminase type 2 through GATA3 defines aggressiveness and Doxorubicin sensitivity in breast cancer

Gianluca Aguiari1, Francesca Crudele2, Cristian Taccioli3, Linda Minotti2, Fabio Corrà2, Jeffrey W. Keillor4, Silvia Grassilli2,5, Carlo Cervellati2, Stefano Volinia2,5, Carlo M. Bergamini1, Nicoletta Bianchi2✉

1. Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy.
2. Department of Translational Medicine, University of Ferrara, Ferrara, Italy.
3. Department of Animal Medicine, Production and Health (MAPS), University of Padua, Padua, Italy.
4. Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada.
5. Laboratory for Advanced Therapy Technologies (LTTA), Via Fossato di Mortara 70, 44124 Ferrara FE, Italy.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Aguiari G, Crudele F, Taccioli C, Minotti L, Corrà F, Keillor JW, Grassilli S, Cervellati C, Volinia S, Bergamini CM, Bianchi N. Dysregulation of Transglutaminase type 2 through GATA3 defines aggressiveness and Doxorubicin sensitivity in breast cancer. Int J Biol Sci 2022; 18(1):1-14. doi:10.7150/ijbs.64167. Available from

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Graphic abstract

The role of transglutaminase type 2 in cell physiology is related to protein transamidation and signal transduction (affecting extracellular, intracellular and nuclear processes) aided by the expression of truncated isoforms and of two lncRNAs with regulatory functions.

In breast cancer TG2 is associated with disease progression supporting motility, epithelial-mesenchymal transition, invasion and drug resistance. The aim of his work is to clarify these issues by emphasizing the interconnections among TGM2 variants and transcription factors associated with an aggressive phenotype, in which the truncated TGH isoform correlates with malignancy. TGM2 transcripts are upregulated by several drugs in MCF-7, but only Doxorubicin is effective in MDA-MB-231 cells. These differences reflect the expression of GATA3, as demonstrated by silencing, suggesting a link between this transcription factor and gene dysregulation. Of note, NC9, an irreversible inhibitor of enzymatic TG2 activities, emerges to control NF-ĸB and apoptosis in breast cancer cell lines, showing potential for combination therapies with Doxorubicin.

Keywords: Transglutaminase variants, breast cancer, GATA3, drug resistance, NC9