PAI‐1 induces Src inhibitor resistance via CCL5 in HER2‐positive breast cancer cells

• Published in: Cancer science 2018-06, Vol.109 (6), p.1949-1957
• Main Authors: Fang, Hehui, Jin, Juan, Huang, Doudou, Yang, Fang, Guan, Xiaoxiang
• Format: Article
• Language: English
• Subjects: Animals; Benzodioxoles - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer therapies; CCL5; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Movement - genetics; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Chemokine CCL5 - genetics; Chemokine CCL5 - metabolism; Chemokines; Chemotherapy; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enzyme Inhibitors - pharmacology; ErbB-2 protein; Experiments; Female; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - drug effects; Humans; Kinases; Medical prognosis; Mice, Inbred BALB C; Mice, Nude; Original; Ovarian cancer; PAI‐1; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen activator inhibitors; Protein-tyrosine kinase; Quinazolines - pharmacology; Receptor, ErbB-2 - metabolism; Signal transduction; Src inhibitor; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13593

Tyrosine kinase Src is overexpressed and activated in various tumors, including breast cancer, and is supposed to promote cancer formation and development. Src inhibitors have been developed recently and have shown efficacy in breast cancer as a single agent or in combination with anti‐HER2 antibodies or chemotherapy. Unfortunately, the potency of Src inhibitor is limited by the development of drug resistance. In our study, we established an Src inhibitor saracatinib‐resistant breast cancer cell line (SKBR‐3/SI) for the first time and by evaluating mRNA expression profile, we found that plasminogen activator inhibitor‐1 (PAI‐1) was upregulated in saracatinib‐resistant cells compared to the parent cells. Further study demonstrated that PAI‐1 might induce saracatinib resistance in breast cancer cells by increasing the secretion of chemokine (C‐C motif) ligand 5 (CCL5). Functional assays showed that PAI‐1 and CCL5 overexpression promoted cell proliferation and migration in breast cancer cells, while inhibition of PAI‐1 and CCL5 decreased cell proliferation and migration in saracatinib‐resistant cells. We also showed that targeting PAI‐1 or CCL5 could reverse saracatinib resistance, which deserves more attention in clinical settings. We first found that PAI‐1 was upregulated in saracatinib‐resistant cells compared to the parent cells. Further study demonstrated that PAI‐1 might induce saracatinib resistance in breast cancer cells by increasing the secretion of CCL5.