Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: Significance in claudin-low breast cancer cells

Molecular Cancer

Research

Dilek Colak¹  Olfat Al-Harazi¹  Asma Tulbah²  Taher Al-Tweigeri³  Abdullah Alsuliman⁴  Hanaa Fitwi⁴  Monther Al-Alwan⁵  Hazem Ghebeh⁵ 

[1] Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia;

关键词: CD274;    Epithelial to Mesenchymal Transition;    Claudin-low;    PI3K;    TGF-β1;    Breast Cancer;   

DOI  :  10.1186/s12943-015-0421-2

 received in 2015-01-20, accepted in 2015-07-27,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe T-cell inhibitory molecule PD-L1 (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients. However, the mechanism that regulates PD-L1 expression in this group of patients is still not well-identified.MethodsWe have used loss and gain of function gene manipulation approach, multi-parametric flow cytometry, large scale gene expression dataset analysis and immunohistochemistry of breast cancer tissue sections.ResultsInduction of epithelial to mesenchymal transition (EMT) in human mammary epithelial cells upregulated PD-L1 expression, which was dependent mainly on the activation of the PI3K/AKT pathway. Interestingly, gene expression signatures available from large cohort of breast tumors showed a significant correlation between EMT score and the PD-L1 mRNA level (p < 0.001). Strikingly, very strong association (p < 0.0001) was found between PD-L1 expression and claudin-low subset of breast cancer, which is known to have high EMT score. On the protein level, significant correlation was found between PD-L1 expression and standard markers of EMT (p = 0.005) in 67 breast cancer patients. Importantly, specific downregulation of PD-L1 in claudin-low breast cancer cells showed signs of EMT reversal as manifested by CD44 and Vimentin downregulation and CD24 upregulation.ConclusionsWe have demonstrated a bidirectional effect between EMT status and PD-L1 expression especially in claudin-low subtype of breast cancer cells. Our findings highlights the potential dual benefit of anti-PD-L1 particularly in this subset of breast cancer patients that will likely benefit more from anti-PD-L1 targeted therapy as well as in monitoring biological changes upon treatment.

【 授权许可】

CC BY   
© Alsuliman et al. 2015