Epigenetic regulation of breast ductal carcinoma in situ by miR‐217 through DNMT1 and Hedgehog‐GLI pathway

Ductal carcinoma in situ (DCIS) is a noninvasive precursor of breast cancer with a high potential for progression. Aberrant DNA methylation plays a pivotal role in early tumorigenesis, yet the regulatory mechanisms remain incompletely defined. Integrated bioinformatic analysis of methylation and transcriptomic datasets identified miR-217 as a candidate regulator of DNA methyltransferase 1 (DNMT1). Functional validation was conducted through RT-qPCR, dual-luciferase reporter assays, methylation-specific PCR, chromatin immunoprecipitation, and phenotypic assays in ZR-75-1 cells. An in vivo xenograft model using nude mice was employed to verify the regulatory axis. Expression of miR-217 was significantly reduced in DCIS tissues and inversely correlated with DNMT1 levels. Direct binding between miR-217 and the 3' untranslated region of DNMT1 was confirmed. Overexpression of miR-217 suppressed DNMT1, resulting in hypomethylation of the teashirt zinc finger homeobox 2 (TSHZ2) promoter and restoration of TSHZ2 expression. Elevated TSHZ2 inhibited Hedgehog-GLI signaling, thereby reducing cell proliferation, migration, invasion, and tumorigenic potential. Reintroduction of DNMT1 or activation of Hedgehog-GLI signaling reversed these effects. In vivo, miR-217 overexpression suppressed tumor growth, downregulated DNMT1 and GLI1, and increased apoptosis. The miR-217/DNMT1/TSHZ2/Hedgehog-GLI signaling axis modulates DCIS progression by epigenetically reprogramming oncogenic pathways. Targeting this axis may offer a promising strategy for DCIS treatment.