Targeting mitochondrial RNA polymerase for triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited therapeutic options, lacking effective molecular targets. Recent studies have highlighted the critical role of mitochondrial metabolism, particularly oxidative phosphorylation, in TNBC progression. Mitochondrial RNA polymerase (POLRMT) has been implicated in maintaining mitochondrial function and stabilizing oxidative phosphorylation complexes. Targeting POLRMT offers a promising strategy to disrupt the heightened metabolic demands of tumors. Kaplan-Meier survival analysis revealed that elevated POLRMT levels were specifically associated with poor prognosis in TNBC patients. The Cancer Genome Atlas cohorts revealed that POLRMT transcripts are upregulated in TNBC tissues, and this enzyme overexpression was linked to hypomethylation of the cg23000464 site in the promoter region. We applied cell proliferation inhibition assays to investigate the potential anti-TNBC activity of targeted siRNA, an inhibitor of mitochondrial transcription (IMT) and mitochondrial protease targeting chimera (MtPTAC). Consistent with the silencing of POLRMT using siRNA both IMT and MtPTAC effectively suppress mitochondrial transcription, impacting oxidative phosphorylation, cell proliferation, and clonogenic ability in TNBC cells. In addition to eliciting comparable effects on cell phenotypes as IMT, MtPTAC selectively degrades POLRMT and inhibits the growth of IMT-resistant cells. POLRMT may represent a promising therapeutic target for TNBC, and MtPTAC could demonstrate promising application prospects. SIGNIFICANCE STATEMENT: This study shows that mitochondrial RNA polymerase (POLRMT) overexpression-linked to promoter hypomethylation-is associated with poor patient prognosis. Silencing or inhibiting POLRMT disrupts mitochondrial transcription, impairing oxidative phosphorylation, cell proliferation, and clonogenicity. Moreover, mitochondrial protease targeting chimera selectively degrades POLRMT and overcomes resistance to conventional inhibitors, underscoring its potential as an effective treatment option for aggressive triple-negative breast cancer.