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
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