miR-506-loaded gelatin nanospheres target PENK and inactivate the ERK/Fos signaling pathway to suppress triple-negative breast cancer aggressiveness.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Some microRNAs (miRNAs) were abnormally expressed in TNBC, and they are closely related to the occurrence and progression of TNBC. Here, we found that miR-506 was significantly downregulated in TNBC and relatively lower miR-506 expression predicted a poorer prognosis. Moreover, we found that miR-506 could inhibit MDA-MB-231 cell viability, colony formation, migration, and invasion, and suppress the ERK/Fos oncogenic signaling pathway through upregulating its direct target protein proenkephalin (PENK). Therefore, miR-506 was proposed as a nucleic acid drug for TNBC therapy. However, miRNA is unstable in vivo, which limiting its application as a therapeutic drug via conventional oral or injected therapies. Here, a gelatin nanosphere (GN) delivery system was applied for the first time to load exogenous miRNA. Exogenous miR-506 mimic was loaded on GNs and injected into the in situ TNBC animal model, and the miR-506 could achieve sustained and controlled release. The results confirmed that overexpression of miR-506 and PENK in vivo through loading on GNs inhibited in situ triple-negative breast tumor growth and metastasis significantly in the xenograft model. Moreover, we indicated that the ERK/Fos signaling pathway was intensively inactivated after overexpression of miR-506 and PENK both in vitro and in vivo, which was further validated by the ERK1/2-specific inhibitor SCH772984. In conclusion, this study demonstrates that miR-506-loaded GNs have great potential in anti-TNBC aggressiveness therapy.