Journal article
Blocking Gi/o-Coupled Signaling Eradicates Cancer Stem Cells and Sensitizes Breast Tumors to HER2-Targeted Therapies to Inhibit Tumor Relapse
Cancers, Vol.14(7), p.1719
03/28/2022
DOI: 10.3390/cancers14071719
PMCID: PMC8997047
PMID: 35406489
Abstract
Cancer stem cells (CSCs) are a small subpopulation of cells within tumors that are resistant to anti-tumor therapies, making them a likely origin of tumor relapse after treatment. In many cancers including breast cancer, CSC function is regulated by G protein-coupled receptors (GPCRs), making GPCR signaling an attractive target for new therapies designed to eradicate CSCs. Yet, CSCs overexpress multiple GPCRs that are redundant in maintaining CSC function, so it is unclear how to target all the various GPCRs to prevent relapse. Here, in a model of HER2+ breast cancer (i.e., transgenic MMTV-Neu mice), we were able to block the tumorsphere- and tumor-forming capability of CSCs by targeting GPCRs coupled to Gi/o proteins (Gi/o-GPCRs). Similarly, in HER2+ breast cancer cells, blocking signaling downstream of Gi/o-GPCRs in the PI3K/AKT and Src pathways also enhanced HER2-targeted elimination of CSCs. In a proof-of-concept study, when CSCs were selectively ablated (via a suicide gene construct), loss of CSCs from HER2+ breast cancer cell populations mimicked the effect of targeting Gi/o-GPCR signaling, suppressing their capacity for tumor initiation and progression and enhancing HER2-targeted therapy. Thus, targeting Gi/o-GPCR signaling in HER2+ breast cancer is a promising approach for eradicating CSCs, enhancing HER2+ targeted therapy and blocking tumor reemergence.
Details
- Title: Subtitle
- Blocking Gi/o-Coupled Signaling Eradicates Cancer Stem Cells and Sensitizes Breast Tumors to HER2-Targeted Therapies to Inhibit Tumor Relapse
- Creators
- Cancan Lyu - University of IowaYuanchao Ye - University of IowaRonald J Weigel - University of IowaSonghai Chen - The Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Cancers, Vol.14(7), p.1719
- DOI
- 10.3390/cancers14071719
- PMID
- 35406489
- PMCID
- PMC8997047
- NLM abbreviation
- Cancers (Basel)
- ISSN
- 2072-6694
- eISSN
- 2072-6694
- Grant note
- BC151478 / United States Department of Defense R01CA207889 / NIH HHS
- Language
- English
- Date published
- 03/28/2022
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Iowa Neuroscience Institute; Surgery; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984242657102771
Metrics
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