A novel role of ADGRF1 (GPR110) in promoting cellular quiescence and chemoresistance in human epidermal growth factor receptor 2-positive breast cancer.
Animals
Breast Neoplasms
/ genetics
Carcinogenesis
/ genetics
Cell Cycle Checkpoints
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Drug Resistance, Neoplasm
/ genetics
Female
G1 Phase
/ genetics
Humans
Mice
Mice, Nude
Oncogene Proteins
/ genetics
Receptor, ErbB-2
/ genetics
Receptors, G-Protein-Coupled
/ genetics
Resting Phase, Cell Cycle
/ genetics
Signal Transduction
/ genetics
ADGRF1
GPR110
HER2
breast cancer
chemoresistance
quiescence
tumorigenesis
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
16
05
2021
received:
12
01
2021
accepted:
19
05
2021
entrez:
10
6
2021
pubmed:
11
6
2021
medline:
17
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34110646
doi: 10.1096/fj.202100070R
pmc: PMC8218746
mid: NIHMS1707858
doi:
Substances chimiques
ADGRF1 protein, human
0
Oncogene Proteins
0
Receptors, G-Protein-Coupled
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e21719Subventions
Organisme : NCI NIH HHS
ID : P50 CA058183
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA186784
Pays : United States
Informations de copyright
© 2021 Federation of American Societies for Experimental Biology.
Références
Cell Rep. 2017 Nov 21;21(8):2183-2197
pubmed: 29166609
Ann N Y Acad Sci. 2019 Nov;1456(1):80-95
pubmed: 31365134
Nat Rev Cancer. 2007 Feb;7(2):79-94
pubmed: 17251915
Cell Signal. 2015 Dec;27(12):2579-88
pubmed: 26321231
BMC Cancer. 2010 Feb 11;10:40
pubmed: 20149256
J Natl Cancer Inst. 2007 May 2;99(9):694-705
pubmed: 17470737
Handb Exp Pharmacol. 2016;234:147-178
pubmed: 27832488
Pathol Res Pract. 2019 Mar;215(3):539-545
pubmed: 30638950
J Clin Med. 2019 Oct 24;8(11):
pubmed: 31652963
J Biol Chem. 2013 Dec 13;288(50):35736-48
pubmed: 24178298
Bioinformation. 2015 May 28;11(5):229-35
pubmed: 26124566
Dev Cell. 2009 Oct;17(4):494-504
pubmed: 19853563
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8561-6
pubmed: 15939874
Cancer Res. 2013 Oct 15;73(20):6206-18
pubmed: 24008316
Commun Biol. 2020 Mar 6;3(1):109
pubmed: 32144388
Cancer Res. 2013 Aug 1;73(15):4885-97
pubmed: 23737486
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):128-38
pubmed: 17085047
J Neuroinflammation. 2019 Nov 15;16(1):225
pubmed: 31730008
Mol Cell Endocrinol. 2011 Apr 10;336(1-2):162-8
pubmed: 21111774
Nucleic Acids Res. 2019 Jul 2;47(W1):W199-W205
pubmed: 31114916
Nat Commun. 2016 May 10;7:11479
pubmed: 27161491
FASEB J. 2008 Mar;22(3):741-51
pubmed: 17928360
Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3665-70
pubmed: 21307310
Sci Signal. 2013 May 21;6(276):re3
pubmed: 23695165
Handb Exp Pharmacol. 2016;234:127-146
pubmed: 27832487
Cancer Lett. 2009 Nov 1;284(2):122-30
pubmed: 19303207
Br J Cancer. 2019 Feb;120(3):331-339
pubmed: 30555156
Nat Commun. 2016 Oct 19;7:13123
pubmed: 27759003
Proc Natl Acad Sci U S A. 2015 May 12;112(19):6194-9
pubmed: 25918380
Cancers (Basel). 2011 Feb 28;3(1):913-26
pubmed: 24212646
Breast Cancer Res. 2011;13(6):R121
pubmed: 22123186
Gen Comp Endocrinol. 2005 May 15;142(1-2):94-101
pubmed: 15862553
Nat Rev Drug Discov. 2017 Jan;16(1):19-34
pubmed: 27910877
Handb Exp Pharmacol. 2016;234:369-396
pubmed: 27832497
J Biol Chem. 2017 Mar 17;292(11):4383-4394
pubmed: 28154189
ACS Pharmacol Transl Sci. 2020 Jan 13;3(1):29-42
pubmed: 32259086
Breast Cancer Res. 2011 Aug 31;13(4):R84
pubmed: 21884573
Breast Cancer Res Treat. 2018 Jul;170(2):279-292
pubmed: 29574636
Front Oncol. 2019 Jul 10;9:626
pubmed: 31355143
Biochem Biophys Res Commun. 2017 Sep 16;491(2):349-354
pubmed: 28728843
Am J Cancer Res. 2017 Mar 01;7(3):433-447
pubmed: 28401002
J Biol Chem. 2001 Sep 7;276(36):33854-60
pubmed: 11457838
Mol Pharmacol. 2018 May;93(5):477-488
pubmed: 29476042
Nat Rev Drug Discov. 2011 Aug 01;10(8):579-90
pubmed: 21804595
Mol Cancer Res. 2019 Nov;17(11):2318-2330
pubmed: 31420371
Stem Cell Rev Rep. 2020 Dec;16(6):1185-1207
pubmed: 32894403
Oncogene. 2015 Feb 26;34(9):1160-73
pubmed: 24662820
Nat Rev Drug Discov. 2017 Dec;16(12):829-842
pubmed: 29075003
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
pubmed: 10592173
Nat Med. 2018 May;24(4):505-511
pubmed: 29578538
Stem Cells Int. 2016;2016:1740936
pubmed: 27418931
PLoS One. 2011;6(10):e26552
pubmed: 22028904
Cell Rep. 2018 Apr 17;23(3):808-822
pubmed: 29669286
Med Sci Monit. 2018 Jul 27;24:5216-5224
pubmed: 30052620
J Biol Chem. 2020 Oct 9;295(41):14065-14083
pubmed: 32763969
Blood. 2010 Dec 2;116(23):4874-84
pubmed: 20699438
Nucleic Acids Res. 2018 Jan 4;46(D1):D956-D963
pubmed: 29136207
Cell. 2015 Oct 8;163(2):506-19
pubmed: 26451490
Cancer. 2018 Oct 15;124(20):4080-4089
pubmed: 30204251
Cell Stem Cell. 2017 Nov 2;21(5):650-664.e8
pubmed: 29100014