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

Breast Cancer Research

Vivian Wang¹  Khldoun Bakdounes¹  Jean-Jacques Lebrun¹  Jun Tian¹  Suhad Ali¹  Baharak Khadang¹  Julien Boudreault¹  Ni Wang¹ 

[1] Department of Medicine, McGill University Health Center, Cancer Research Program, 1001 Decarie Blvd, Bloc E, Suite E02.6224, H4A 3J1, Montreal, QC, Canada;

关键词: COX-2;    Celecoxib;    Breast cancer;    TNBC;    Drug resistance;    MGFE8;    KLK5/7;   

DOI  :  10.1186/s13058-021-01401-2

来源: Springer

【 摘 要 】

BackgroundCyclooxygenase 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.MethodsBy 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.ResultsWe 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.ConclusionsTogether, our study supports the establishment and use of novel COX-2 inhibitor-based combination therapies as future strategies for TNBC treatment.

【 授权许可】

CC BY