Reduced expression of the murine HLA-G homolog Qa-2 is associated with malignancy, epithelialmesenchymal transition and stemness in breast cancer cells.
Author: L. da Silva, Istéfani; Montero Montero, Lucía; Martín Villar, Ester; Martín Pérez, Jorge; Sainz, Bruno; Renart, Jaime; Toscano Simões, Renata; Soares Veloso, Émerson; Salviano Teixeira, Cláudia; C. de Oliveira, Mônica; Ferreira, Enio; Quintanilla, Miguel
Abstract: Qa-2 is believed to mediate a protective immune response against cancer; however, little is known
about the role of Qa-2 in tumorigenesis. Here, we used 4T1 breast cancer cells to study the involvement
of Qa-2 in tumor progression in a syngeneic host. Qa-2 expression was reduced during in vivo tumor
growth and in cell lines derived from 4T1-induced tumors. Tumor-derived cells elicited an epithelialmesenchymal
transition associated with upregulation of Zeb1 and Twist1/2 and enhanced tumor
initiating and invasive capacities. Furthermore, these cells showed increased stem characteristics, as
demonstrated by upregulation of Hes1, Sox2 and Oct3/4, and enrichment of CD44high/CD24median/low
cells. Remarkably, Qa-2 cell-surface expression was excluded from the CD44high/CD24median/low
subpopulation. Tumor-derived cells showed increased Src activity, and treatment of these cells with the
Src kinase inhibitor PP2 enhanced Qa-2 but reduced Sox2 and CD44high/CD24median/low expression levels,
suggesting that Src signaling, while positively associated with stemness, negatively regulates Qa-2
expression in breast cancer. Finally, overexpression of the Qa-2 family member Q7 on the cell surface
slowed down in vivo tumor growth and reduced the metastatic potential of 4T1 cells. These results
suggest an anti-malignant role for Qa-2 in breast cancer development, which appears to be absent from
cancer stem cells.
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