Journal article
Fibroblast growth receptor 1 is regulated by G-quadruplex in metastatic breast cancer
Communications biology, Vol.7(1), 963
08/09/2024
DOI: 10.1038/s42003-024-06602-x
PMCID: PMC11316068
PMID: 39122837
Abstract
Limiting cellular plasticity is of key importance for the therapeutic targeting of metastatic breast cancer (MBC). Fibroblast growth receptor (FGFR) is a critical molecule in cellular plasticity and potent inhibitors of FGFR enzymatic activity have been developed, but kinase independent functions for this receptor also contribute to MBC progression. Herein, we evaluated several FGFR inhibitors and find that while FGFR-targeted kinase inhibitors are effective at blocking ligand-induced cell growth, dormant cells persist eventually giving rise to MBC progression. To more broadly target FGFR and cellular plasticity, we examined the FGFR1 proximal promoter, and found several sequences with potential to form G-quadruplex secondary structures. Circular dichroism was used to verify formation of G-quadruplex in the FGFR1 proximal promoter. Importantly, use of the clinical G-quadruplex-stabilizing compound, CX-5461, stabilized the FGFR1 G-quadruplex structures, blocked the transcriptional activity of the FGFR1 proximal promoter, decreased FGFR1 expression, and resulted in potent inhibition of pulmonary tumor formation. Overall, our findings suggest G-quadruplex-targeted compounds could be a potential therapeutic strategy to limit the cellular plasticity of FGFR1 overexpressing MBC.This study demonstrates the regulation of FGFR1 expression in metastatic breast cancer through the stabilization of G-quadruplex in its proximal promoter.
Details
- Title: Subtitle
- Fibroblast growth receptor 1 is regulated by G-quadruplex in metastatic breast cancer
- Creators
- Hang Lin - Purdue University West LafayetteMuhammad Hassan Safdar - Purdue University West LafayetteSarah Washburn - Purdue University West LafayetteSaeed S Akhand - Purdue University West LafayetteJonathan Dickerhoff - Purdue University West LafayetteMitchell Ayers - Purdue University West LafayetteMarvis Monteiro - Purdue University West LafayetteLuis Solorio - Purdue University West LafayetteDanzhou Yang - Purdue University West LafayetteMichael K Wendt - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Communications biology, Vol.7(1), 963
- DOI
- 10.1038/s42003-024-06602-x
- PMID
- 39122837
- PMCID
- PMC11316068
- NLM abbreviation
- Commun Biol
- ISSN
- 2399-3642
- eISSN
- 2399-3642
- Publisher
- Nature Publishing Group
- Grant note
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI): R01CA271597, R01CA232589, R01CA177585, U01CA240346 National Cancer Institute: P30CA023168
This work was supported by the National Cancer Institute (R01CA271597, R01CA232589, R01CA177585, and U01CA240346). We also acknowledge the support of the Purdue Institute for Cancer Research via its NIH NCI grant (P30CA023168). We also acknowledge personnel and the use of the facilities within the Bindley Bioscience Center, a core facility of the NIH-funded Indiana Clinical and Translational Sciences Institute.DAS:All data generated or analyzed during this study are included in this published article (and its supplementary data 1 file).
- Language
- English
- Date published
- 08/09/2024
- Academic Unit
- Holden Comprehensive Cancer Center; Internal Medicine
- Record Identifier
- 9984696780602771
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