Dataset Information

ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer

ABSTRACT: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and the lack of specific signature makes difficult the development of targeted therapeutic strategy. We previously found that PRICKLE1, an evolutionary conserved protein acting as a regulator of vertebrate development, is upregulated in TNBC. Proteomic approaches allowed us to decipher the protein complex associated to PRICKLE1 in TNBC. Within that complex, we identified a large subset of proteins involved in the regulation of Rho-GTPase family members. We build a metagene with regulators of small G-protein activity and we found that this metagene is overexpressed in TNBC and is a poor prognosis marker. We analyzed the combination of the metagene expression and PRICKLE1 expression and identified that combined expression of ECT2 and PRICKLE1 provides a worst prognosis than PRICKLE1 expression alone in TNBC. ECT2 is a GEF for Rac1 and we showed that PRICKLE1 regulate the enzymatic activity of ECT2. Finally, we also observed that Ect2 and Prickle1 are functionally connected during evolution since both act synergistically to coordinate cellular movement during vertebrate gastrulation. Our results demonstrate the pivotal role of PRICKLE1 in TNBC and build the path for development of targeted therapeutic strategies to heal TNBC patients.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: AUDEBERT Stephane

LAB HEAD: Audebert Stephane

PROVIDER: PXD011253 | Pride | 2019-10-15

REPOSITORIES: Pride

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ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer.

Daulat Avais M AM Finetti Pascal P Revinski Diego D Silveira Wagner Mônica M Camoin Luc L Audebert Stéphane S Birnbaum Daniel D Kodjabachian Laurent L Borg Jean-Paul JP Bertucci François F

British journal of cancer 20190411 9

<h4>Background</h4>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.<h4>Methods</h4>We used a proteomic approach t ...[more]

PMID: 30971775

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Project description:Most patients with triple negative breast cancer (TNBC) fail to respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression remain elusive. Here, we identify aberrant B7H3 glycosylation and found N-glycosylation of B7H3 at NXT motif sites are responsible for its protein stability and immunosuppression in TNBC tumors. Mechanistically, fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression could be physiologically significant and clinically relevant in TNBC patients. Notably, combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These suggest targeting FUT8-B7H3 axis can be a promising strategy for improving anti-tumor immune responses in TNBC patients. To obtain the direct evidence that B7H3 is N-glycosylated in TNBC cells, we analysed the peptides of purified human B7H3 protein from B7H3-WT re-expressed and B7H3-8NQ re-expressed MDA-MB-231 cell lines by Nanoscale liquid chromatography coupled to tandem MS (nano LC-MS/MS). The result showed that there were eight N-glycosylation sites (Asn positions 91, 104, 189, 215, 309, 322, 407, and 433) in B7H3-WT cells, but not in B7H3-8NQ cells, as determined by Asn to Asp conversion after PNGase F treatment. As B7H3 contains a nearly exact tandem duplication of the IgV-IgC domain, there were four pairs of N-glycosylation sites identified through identical peptide sequence, including N91 and N309, N104 and N322, N189 and N407, and N215 and N433, in each of the IgV-IgC domains. Together, the results indicate that B7H3 is exclusively N-glycosylated at these four pairs of glycosylation sites in TNBC cells.

			Action	DRS
	1_GFP.msf	Msf
	1_GFP.raw	Raw
	1_GFPPrk.msf	Msf
	1_GFPPrk.raw	Raw
	1_GFPPrk_171216092913.msf	Msf