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.