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Breast Cancer Research
Published in: Breast Cancer Research 1/2021

01-12-2021 | Metastasis | Research article

Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition

Authors: Jun Tian, Vivian Wang, Ni Wang, Baharak Khadang, Julien Boudreault, Khldoun Bakdounes, Suhad Ali, Jean-Jacques Lebrun

Published in: Breast Cancer Research | Issue 1/2021

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Abstract

Background

Cyclooxygenase 2 (COX-2) promotes stemness in triple negative breast cancer (TNBC), highlighting COX-2 as a promising therapeutic target in these tumors. However, to date, clinical trials using COX-2 inhibitors in breast cancer only showed variable patient responses with no clear significant clinical benefits, suggesting underlying molecular mechanisms contributing to resistance to COX-2 inhibitors.

Methods

By combining in silico analysis of human breast cancer RNA-seq data with interrogation of public patient databases and their associated transcriptomic, genomic, and clinical profiles, we identified COX-2 associated genes whose expression correlate with aggressive TNBC features and resistance to COX-2 inhibitors. We then assessed their individual contributions to TNBC metastasis and resistance to COX-2 inhibitors, using CRISPR gene knockout approaches in both in vitro and in vivo preclinical models of TNBC.

Results

We identified multiple COX-2 associated genes (TPM4, RGS2, LAMC2, SERPINB5, KLK7, MFGE8, KLK5, ID4, RBP1, SLC2A1) that regulate tumor lung colonization in TNBC. Furthermore, we found that silencing MFGE8 and KLK5/7 gene expression in TNBC cells markedly restored sensitivity to COX-2 selective inhibitor both in vitro and in vivo.

Conclusions

Together, our study supports the establishment and use of novel COX-2 inhibitor-based combination therapies as future strategies for TNBC treatment.
Appendix
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Metadata
Title
Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition
Authors
Jun Tian
Vivian Wang
Ni Wang
Baharak Khadang
Julien Boudreault
Khldoun Bakdounes
Suhad Ali
Jean-Jacques Lebrun
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2021
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-021-01401-2

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