ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer.
Animals
Biomarkers, Tumor
/ genetics
Evolution, Molecular
Female
Humans
LIM Domain Proteins
/ genetics
Middle Aged
Prognosis
Proteome
/ metabolism
Proto-Oncogene Proteins
/ genetics
RNA, Messenger
/ biosynthesis
Transcriptome
Triple Negative Breast Neoplasms
/ genetics
Tumor Suppressor Proteins
/ genetics
Xenopus laevis
rac1 GTP-Binding Protein
/ metabolism
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
06
12
2018
accepted:
18
03
2019
revised:
08
03
2019
pubmed:
12
4
2019
medline:
29
2
2020
entrez:
12
4
2019
Statut:
ppublish
Résumé
Triple-negative breast cancers (TNBC) are poor-prognosis tumours candidate to chemotherapy as only systemic treatment. We previously found that PRICKLE1, a prometastatic protein involved in planar cell polarity, is upregulated in TNBC. We investigated the protein complex associated with PRICKLE1 in TNBC to identify proteins possibly involved in metastatic dissemination, which might provide new prognostic and/or therapeutic targets. We used a proteomic approach to identify protein complexes associated with PRICKLE1. The mRNA expression levels of the corresponding genes were assessed in 8982 patients with invasive primary breast cancer. We then characterised the molecular interaction between PRICKLE1 and the guanine nucleotide exchange factor ECT2. Finally, experiments in Xenopus were carried out to determine their evolutionarily conserved interaction. Among the PRICKLE1 proteins network, we identified several small G-protein regulators. Combined analysis of the expression of PRICKLE1 and small G-protein regulators had a strong prognostic value in TNBC. Notably, the combined expression of ECT2 and PRICKLE1 provided a worst prognosis than PRICKLE1 expression alone in TNBC. PRICKLE1 regulated ECT2 activity and this interaction was evolutionary conserved. This work supports the idea that an evolutionarily conserved signalling pathway required for embryogenesis and activated in cancer may represent a suitable therapeutic target.
Sections du résumé
BACKGROUND
Triple-negative breast cancers (TNBC) are poor-prognosis tumours candidate to chemotherapy as only systemic treatment. We previously found that PRICKLE1, a prometastatic protein involved in planar cell polarity, is upregulated in TNBC. We investigated the protein complex associated with PRICKLE1 in TNBC to identify proteins possibly involved in metastatic dissemination, which might provide new prognostic and/or therapeutic targets.
METHODS
We used a proteomic approach to identify protein complexes associated with PRICKLE1. The mRNA expression levels of the corresponding genes were assessed in 8982 patients with invasive primary breast cancer. We then characterised the molecular interaction between PRICKLE1 and the guanine nucleotide exchange factor ECT2. Finally, experiments in Xenopus were carried out to determine their evolutionarily conserved interaction.
RESULTS
Among the PRICKLE1 proteins network, we identified several small G-protein regulators. Combined analysis of the expression of PRICKLE1 and small G-protein regulators had a strong prognostic value in TNBC. Notably, the combined expression of ECT2 and PRICKLE1 provided a worst prognosis than PRICKLE1 expression alone in TNBC. PRICKLE1 regulated ECT2 activity and this interaction was evolutionary conserved.
CONCLUSIONS
This work supports the idea that an evolutionarily conserved signalling pathway required for embryogenesis and activated in cancer may represent a suitable therapeutic target.
Identifiants
pubmed: 30971775
doi: 10.1038/s41416-019-0448-z
pii: 10.1038/s41416-019-0448-z
pmc: PMC6734648
doi:
Substances chimiques
Biomarkers, Tumor
0
ECT2 protein, human
0
LIM Domain Proteins
0
PRICKLE1 protein, human
0
Proteome
0
Proto-Oncogene Proteins
0
RAC1 protein, human
0
RNA, Messenger
0
Tumor Suppressor Proteins
0
rac1 GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
931-940Références
Development. 1999 Oct;126(19):4257-65
pubmed: 10477294
J Cell Sci. 2016 Aug 15;129(16):3115-29
pubmed: 27378169
Cancer Cell. 2017 Feb 13;31(2):256-269
pubmed: 28110998
J Cell Biol. 2008 Jan 14;180(1):221-32
pubmed: 18195109
J Clin Invest. 2011 Jul;121(7):2750-67
pubmed: 21633166
Dev Biol. 2006 May 1;293(1):252-67
pubmed: 16554046
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17437-42
pubmed: 19805078
Cell. 2012 Dec 21;151(7):1542-56
pubmed: 23260141
Cell. 2009 Apr 17;137(2):295-307
pubmed: 19379695
J Embryol Exp Morphol. 1982 Apr;68:37-57
pubmed: 6809878
Semin Cell Dev Biol. 2015 Jun;42:78-85
pubmed: 25986055
J Clin Pathol. 2018 May;71(5):442-445
pubmed: 29051317
Nat Biotechnol. 2014 Mar;32(3):223-6
pubmed: 24727771
Oncogene. 2014 Jul 31;33(31):4021-35
pubmed: 24037532
Curr Biol. 2018 May 7;28(9):R570-R580
pubmed: 29738735
Mol Cell Biol. 2012 Jan;32(1):173-85
pubmed: 22037766
Dev Cell. 2015 Nov 9;35(3):383-94
pubmed: 26555057
PLoS Genet. 2015 Mar 12;11(3):e1005022
pubmed: 25763846
Curr Biol. 2003 Apr 15;13(8):674-9
pubmed: 12699625
Nature. 2006 Jan 12;439(7073):220-4
pubmed: 16407953
Br J Cancer. 2005 Aug 22;93(4):387-91
pubmed: 16106245
Cancer Lett. 2014 Dec 1;355(1):70-5
pubmed: 25218596
Curr Biol. 2003 Apr 15;13(8):680-5
pubmed: 12699626
J Cell Biol. 2016 May 23;213(4):463-77
pubmed: 27185833
Curr Biol. 2014 Jan 20;24(2):144-155
pubmed: 24388847
Genes Cancer. 2013 Nov;4(11-12):460-75
pubmed: 24386507
PLoS One. 2011;6(11):e27656
pubmed: 22110708
Nat Rev Mol Cell Biol. 2017 Jun;18(6):375-388
pubmed: 28293032
Cell Mol Life Sci. 2015 Jun;72(11):2075-89
pubmed: 25672900
Dev Cell. 2016 May 23;37(4):311-325
pubmed: 27184734
J Biol Chem. 2011 Mar 11;286(10):8149-57
pubmed: 21189248
Oncogene. 2009 Oct 15;28(41):3597-607
pubmed: 19617897
Dev Cell. 2002 Jun;2(6):695-706
pubmed: 12062082
Front Oncol. 2018 Jun 14;8:227
pubmed: 29963498
Nature. 2016 Oct 19;538(7625):336-343
pubmed: 27762356
PLoS One. 2017 Oct 31;12(10):e0187356
pubmed: 29088286
EMBO J. 2003 Sep 1;22(17):4409-20
pubmed: 12941693
Biochemistry. 2008 Dec 23;47(51):13524-36
pubmed: 19053268
Nat Commun. 2016 May 26;7:11714
pubmed: 27226243
Mech Dev. 2002 Aug;116(1-2):183-6
pubmed: 12128221
Nature. 2009 Sep 3;461(7260):99-103
pubmed: 19693013