RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells

Chen, F. et al. (2023) RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells. Oncogene, 42(9), pp. 679-692. (doi: 10.1038/s41388-022-02574-6) (PMID:36599922) (PMCID:PMC9957727)

Abstract

Breast cancer stem cells (BCSC) are presumed to be responsible for treatment resistance, tumor recurrence and metastasis of breast tumors. However, development of BCSC-targeting therapies has been held back by their heterogeneity and the lack of BCSC-selective molecular targets. Here, we demonstrate that RAC1B, the only known alternatively spliced variant of the small GTPase RAC1, is expressed in a subset of BCSCs in vivo and its function is required for the maintenance of BCSCs and their chemoresistance to doxorubicin. In human breast cancer cell line MCF7, RAC1B is required for BCSC plasticity and chemoresistance to doxorubicin in vitro and for tumor-initiating abilities in vivo. Unlike Rac1, Rac1b function is dispensable for normal mammary gland development and mammary epithelial stem cell (MaSC) activity. In contrast, loss of Rac1b function in a mouse model of breast cancer hampers the BCSC activity and increases their chemosensitivity to doxorubicin treatment. Collectively, our data suggest that RAC1B is a clinically relevant molecular target for the development of BCSC-targeting therapies that may improve the effectiveness of doxorubicin-mediated chemotherapy.

• Item Type: Articles
• Additional Information: This work was supported by scientific fellowship grant (#2016MaySF722) to AU and project grant (#2013MayPR029) to CS from Breast Cancer Now.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sansom, Professor Owen and Campbell, Dr Andrew
• Authors: Chen, F., Gurler, S. B., Novo, D., Selli, C., Alferez, D. G., Eroglu, S., Pavlou, K., Zhang, J., Sims, A. H., Humphreys, N. E., Adamson, A., Campbell, A., Sansom, O. J., Tournier, C., Clarke, R. B., Brennan, K., Streuli, C. H., and Ucar, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncogene
• Publisher: Springer Nature
• ISSN: 0950-9232
• ISSN (Online): 1476-5594
• Published Online: 05 January 2023
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Oncogene 42(9): 679-692
• Publisher Policy: Reproduced under a Creative Commons License