A novel role of ADGRF1 (GPR110) in promoting cellular quiescence and chemoresistance in human epidermal growth factor receptor 2-positive breast cancer
| Autor: | Hariprasad Thangavel, Rachel Schiff, Sarmistha Nanda, Meghana V. Trivedi, Suhas Vasaikar, Bing Zhang, Carmine De Angelis, Martin Shea, Raksha Bhat, Ambily Gopinathan, Lanfang Qin, Tamika Mitchell, Noor Mazin Abdulkareem |
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| Přispěvatelé: | Abdulkareem, N. M., Bhat, R., Qin, L., Vasaikar, S., Gopinathan, A., Mitchell, T., Shea, M. J., Nanda, S., Thangavel, H., Zhang, B., De Angelis, C., Schiff, R., Trivedi, M. V. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint Carcinogenesis Receptor ErbB-2 medicine.disease_cause Biochemistry Receptors G-Protein-Coupled Mice 0302 clinical medicine Receptor Carcinogenesi Oncogene Proteins education.field_of_study Oncogene Protein chemoresistance Cell cycle Female Signal transduction GPR110 Breast Neoplasm Biotechnology Human Signal Transduction Gs alpha subunit Population Mice Nude Breast Neoplasms Biology tumorigenesi Resting Phase Cell Cycle Article 03 medical and health sciences breast cancer Cell Cycle Checkpoint HER2 Cell Line Tumor Genetics medicine Animals Humans quiescence education Molecular Biology Cell Proliferation ADGRF1 Animal G1 Phase Cancer Cell Cycle Checkpoints medicine.disease 030104 developmental biology Drug Resistance Neoplasm Cancer research 030217 neurology & neurosurgery |
| Zdroj: | FASEB J |
| Popis: | While G protein-coupled receptors (GPCRs) are known to be excellent drug targets, the second largest family of adhesion-GPCRs is less explored for their role in health and disease. ADGRF1 (GPR110) is an adhesion-GPCR and has an important function in neurodevelopment and cancer. Despite serving as a poor predictor of survival, ADGRF1's coupling to G proteins and downstream pathways remain unknown in cancer. We evaluated the effects of ADGRF1 overexpression on tumorigenesis and signaling pathways using two human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC) cell-line models. We also interrogated publicly available clinical datasets to determine the expression of ADGRF1 in various BC subtypes and its impact on BC-specific survival (BCSS) and overall survival (OS) in patients. ADGRF1 overexpression in HER2+ BC cells increased secondary mammosphere formation, soft agar colony formation, and % of Aldefluor-positive tumorigenic population in vitro and promoted tumor growth in vivo. ADGRF1 co-immunoprecipitated with both Gαs and Gαq proteins and increased cAMP and IP1 when overexpressed. However, inhibition of only the Gαs pathway by SQ22536 reversed the pro-tumorigenic effects of ADGRF1 overexpression. RNA-sequencing and RPPA analysis revealed inhibition of cell cycle pathways with ADGRF1 overexpression, suggesting cellular quiescence, as also evidenced by cell cycle arrest at the G0/1 phase and resistance to chemotherapy in HER2+ BC. ADGRF1 was significantly overexpressed in the HER2-enriched BC compared to luminal A and B subtypes and predicted worse BCSS and OS in these patients. Therefore, ADGRF1 represents a novel drug target in HER2+ BC, warranting discovery of novel ADGRF1 antagonists. |
| Databáze: | OpenAIRE |
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