Language
English
Publication Date
6-1-2025
Journal
British Journal of Pharmacology
DOI
10.1111/bph.17463
PMID
39965212
Abstract
Background and purpose: We and others have previously shown that ADGRF1, an adhesion G protein-coupled receptor, is overexpressed and associated with poor survival in many cancers, including human epidermal growth factor receptor-2 (HER2) breast cancer (BC). Also, we have reported the tumour-promoting function of ADGRF1 using preclinical models of HER2+ BC. In this study, we investigated the effect of ADGRF1 overexpression in an orthotopic in vivo model as well as downstream signalling of ADGRF1 in HER2+ BC.
Experimental approach: We utilized a doxycycline (Dox)-induced ADGRF1 overexpression system in HER2+ BC cell lines and performed various in vitro and in vivo studies. Following ADGRF1 overexpression in the presence/absence of Matrigel, laminin-111 or collagen-IV, we performed the mammosphere assay to assess the tumorigenicity of breast epithelial cells, as well as cAMP/IP1 assays and RNA-sequencing, to understand the receptor function and pharmacology. We conducted cross-linking-aided immunoprecipitation and mass spectrometry to confirm the physical interaction between ADGRF1 and the extracellular matrix proteins present in Matrigel.
Key results: We found that ADGRF1 switched from a tumour-promoting to tumour-suppressive function upon interaction with laminin-111. Interaction of ADGRF1 with laminin-111 resulted in inhibition of Gαs coupling and STAT3 phosphorylation, induction of senescence, increase in HER2 expression, and improvement of sensitivity to anti-HER2 drugs in HER2+ BC.
Conclusions: ADGRF1 switches from a tumour-promoting to tumour-suppressive function upon interaction with laminin-111, leading to improvements in sensitivity to anti-HER2 drugs. Leveraging ADGRF1 interactions with laminin-111 may allow the design of novel therapies against ADGRF1 in HER2+ BC.
Keywords
Humans, Breast Neoplasms, Female, Erb-b2 Receptor Tyrosine Kinases, Animals, Receptors, G-Protein-Coupled, Mice, Extracellular Matrix Proteins, Carcinogenesis, Cell Line, Tumor, Laminin, Mice, Nude, ADGRF1, GPCRs, breast cancer, drug target
Published Open-Access
yes
Recommended Citation
Abdulkareem, Noor Mazin; Bhat, Raksha; Castillo, Micah; et al., "Interactions Between ADGRF1 (GPR110) and Extracellular Matrix Proteins Govern Its Effects on Tumorigenesis in HER2-Positive Breast Cancer" (2025). Faculty, Staff and Students Publications. 6542.
https://digitalcommons.library.tmc.edu/baylor_docs/6542