MIR2052HG regulates ERα levels and aromatase inhibitor resistance through LMTK3 by recruiting EGR1

Our previous GWAS using the MA.27 aromatase inhibitors (AIs) adjuvant trial identified SNPs in the lncRNA MIR2052HG associated with breast cancer free interval. Here we report that MIR2052HG depletion in breast cancer cells results in a decrease in LMTK3 expression and cell growth. Mechanistically, MIR2052HG interacts with EGR1 and facilitates its recruitment to the LMTK3 promoter. LMTK3 sustains ER levels by reducing PKC activity, resulting in increased ESR1 transcription mediated through AKT/FOXO3 and reduced ER degradation mediated by the PKC/MEK/ERK/RSK1 pathway. MIR2052HG regulated LMTK3 in a SNP- and aromatase inhibitor - dependent fashion: the variant SNP increased EGR1 binding to LMTK3 promoter in response to androstenedione, relative to wild-type genotype, a pattern that can be reversed by aromatase inhibitor treatment. Finally, LMTK3 overexpression abolished the effect of MIR2052HG on PKC activity and ER levels. These results reveal a direct role of MIR2052HG in LMTK3 regulation and raise the possibility of targeting MIR2052HG or LMTK3 in ER-positive breast cancer.