PD‐L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. Issue 7 (30th June 2017)

• Record Type: Journal Article
• Authors: Almozyan, Sheema; Colak, Dilek; Mansour, Fatmah; Alaiya, Ayodele; Al‐Harazi, Olfat; Qattan, Amal; Al‐Mohanna, Falah; Al‐Alwan, Monther; Ghebeh, Hazem
• Is Part Of: International journal of cancer. Volume 141:Issue 7(2017:Oct. 01)
• Page Start: 1402
• Page End: 1412
• Publication Date: 2017-06-30
• Subjects: PD‐L1 -- cancer stem cells -- stemness -- AKT -- breast cancer -- OCT4A -- Nanog; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.30834
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : The expression of PD‐L1 in breast cancer is associated with estrogen receptor negativity, chemoresistance and epithelial‐to‐mesenchymal transition (EMT), all of which are common features of a highly tumorigenic subpopulation of cancer cells termed cancer stem cells (CSCs). Hitherto, the expression and intrinsic role of PD‐L1 in the dynamics of breast CSCs has not been investigated. To address this issue, we used transcriptomic datasets, proteomics and several in vitro and in vivo assays. Expression profiling of a large breast cancer dataset (530 patients) showed statistically significant correlation ( p < 0.0001, r = 0.36) between PD‐L1 expression and stemness score of breast cancer. Specific knockdown of PD‐L1 using ShRNA revealed its critical role in the expression of the embryonic stem cell transcriptional factors: OCT‐4A, Nanog and the stemness factor, BMI1. Conversely, these factors could be induced upon PD‐L1 ectopic expression in cells that are normally PD‐L1 negative. Global proteomic analysis hinted for the central role of AKT in the biology of PD‐L1 expressing cells. Indeed, PD‐L1 positive effect on OCT‐4A and Nanog was dependent on AKT activation. Most importantly, downregulation of PD‐L1 compromised the self‐renewal capability of breast CSCs in vitro and in vivo as shown by tumorsphere formation assay and extreme limiting dilution assay, respectively. This study demonstrates a novel role for PD‐L1 in sustaining stemness of breast cancer cells and identifies the subpopulation and its associated molecular pathways that would be targeted upon anti‐PD‐L1 therapy. Abstract : What's new? Cancer cells that express the T‐cell inhibitory molecule programmed death‐ligand 1 (PD‐L1) readily escape immune attack. In addition, PD‐L1 expression contributes to chemoresistance and is associated with epithelial‐to‐mesenchymal transition, a process that generates cancer stem cells (CSCs). This study shows that in breast cancer, PD‐L1 expression further plays a direct part in maintaining CSC stemness. In breast cancer cells, PD‐L1 expression sustained stemness factors OCT‐4A and Nanog, via a PI3K/AKT‐dependent pathway, and promoted expression of the stemness controlling factor BMI1, independent of PI3K/AKT. Targeting PD‐L1 could help advance breast cancer therapy, owing to impacts on the pool of breast CSCs.