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Mol Cancer. 2015 Aug 7;14:149. doi: 10.1186/s12943-015-0421-2.

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

Author information

1
Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. absuliman@kfshrc.edu.sa.
2
Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. dcolakkaya@kfshrc.edu.sa.
3
Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. n3509885@kfshrc.edu.sa.
4
Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. n3508575@kfshrc.edu.sa.
5
Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. tulbah@kfshrc.edu.sa.
6
Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. ttwegieri@kfshrc.edu.sa.
7
Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. malwan@kfshrc.edu.sa.
8
College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia. malwan@kfshrc.edu.sa.
9
Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. hghebeh@kfshrc.edu.sa.
10
College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia. hghebeh@kfshrc.edu.sa.

Abstract

BACKGROUND:

The 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.

METHODS:

We 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.

RESULTS:

Induction 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.

CONCLUSIONS:

We 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.

PMID:
26245467
PMCID:
PMC4527106
DOI:
10.1186/s12943-015-0421-2
[Indexed for MEDLINE]
Free PMC Article

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