Interactions between ADGRF1 (GPR110) and extracellular matrix proteins govern its effects on tumorigenesis in HER2-positive breast cancer.

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Tác giả: Noor Mazin Abdulkareem, Tasneem Bawa-Khalfe, Raksha Bhat, Wangjia Cao, Micah Castillo, Preethi Gunaratne, Tahir Hussain, Sung Yun Jung, Hee-Yong Kim, Xinli Liu, Sarmistha Nanda, Alexis Ruiz, Rachel Schiff, Martin Shea, Meghana V Trivedi, Suhas Vasaikar, Jamunarani Veeraraghavan

Ngôn ngữ: eng

Ký hiệu phân loại: 553.453 Tin

Thông tin xuất bản: England : British journal of pharmacology , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 199194

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.
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