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LncRNA BORG:TRIM28 Complexes Drive Metastatic Progression by Inducing α6 Integrin/CD49f Expression in Breast Cancer Stem Cells.

ABSTRACT: Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with its aggressive phenotype being attributed to chemotherapy resistance, metastatic dissemination, and rapid disease recurrence. Breast cancer stem cells (BCSC) are significant contributors to tumor initiation, as well as to the acquisition of aggressive tumorigenic phenotypes, namely due to their ability to self-replicate and to produce heterogeneous differentiated tumor cells. To elucidate the underlying mechanisms that drive BCSC tumorigenicity in TNBC, we identified the long noncoding RNA (lncRNA) B MP/ O P- R esponsive G ene (BORG) as an enhancer of BCSC phenotypes. Indeed, we found BORG expression to: (i) correlate with stem cell markers Nanog, Aldh1a3, and Itga6 (α6 integrin/CD49f); (ii) enhance stem cell phenotypes in murine and human TNBC cells, and (iii) promote TNBC tumor initiation in mice. Mechanistically, BORG promoted BCSC phenotypes through its ability to interact physically with the E3 SUMO ligase TRIM28. Moreover, TRIM28 binding was observed in the promoter region of Itga6, whose genetic inactivation prevented BORG:TRIM28 complexes from: (i) inducing BCSC self-renewal and expansion in vitro, and (ii) eliciting BCSC metastatic outgrowth in the lungs of mice. Collectively, these findings implicate BORG:TRIM28 complexes as novel drivers of BCSC phenotypes in developing and progressing TNBCs. IMPLICATIONS: This work establishes the lncRNA BORG as a driver of BCSC phenotypes and the aggressive behaviors of TNBCs, events critically dependent upon the formation of BORG:TRIM28 complexes and expression of α6 integrin.

SUBMITTER: Parker KA

PROVIDER: S-EPMC8642309 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Central nervous system leukemia (CNS-L) is caused by leukemic cells infiltrating into the meninges or brain parenchyma and remains the main reason for disease relapse. Currently, it is hard to detect CNS-L accurately by clinically available imaging models due to the relatively low amount of tumor cells, confined blood supply, and the inferior glucose metabolism intensity. Recently, integrin α6-laminin interactions have been identified to mediate CNS-L, which suggests that integrin α6 may be a promising molecular imaging target for the detection of CNS-L. The acute lymphoblastic leukemia (ALL) cell line NALM6 stabled and transfected with luciferase was used to establish the CNS-L mouse model. CNS-L-bearing mice were monitored and confirmed by bioluminescence imaging. Three of our previously developed integrin α6-targeted peptide-based molecular imaging agents, Cy5-S5 for near-infrared fluorescence (NIRF), Gd-S5 for magnetic resonance (MR), and 18F-S5 for positron emission tomography (PET) imaging, were employed for the molecular imaging of these CNS-L-bearing mice. Bioluminescence imaging showed a local intensive signal in the heads among CNS-L-bearing mice; meanwhile, Cy5-S5/NIRF imaging produced intensive fluorescence intensity in the same head regions. Moreover, Gd-S5/MR imaging generated superior MR signal enhancement at the site of meninges, which were located between the skull bone and brain parenchyma. Comparatively, MR imaging with the clinically available MR enhancer Gd-DTPA did not produce the distinguishable MR signal in the same head regions. Additionally, 18F-S5/PET imaging also generated focal radio-concentration at the same head regions, which generated nearly 5-times tumor-to-background ratio compared to the clinically available PET radiotracer 18F-FDG. Finally, pathological examination identified layer-displayed leukemic cells in the superficial part of the brain parenchyma tissue, and immunohistochemical staining confirmed the overexpression of the integrin α6 within the lesion. These findings suggest the potential application of these integrin α6-targeted molecular imaging agents for the accurate detection of CNS-L.

Dataset Information

LncRNA BORG:TRIM28 Complexes Drive Metastatic Progression by Inducing α6 Integrin/CD49f Expression in Breast Cancer Stem Cells.

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