Dual Role of LBH589 in Triple-Negative Breast Cancer: Inhibition of Tumor Growth and Enhancement of Antitumor Immunity.

BACKGROUND: Epigenetic dysregulation, particularly aberrant histone deacetylase (HDAC) activity, plays a critical role in the progression of breast cancer. Although HDAC inhibitors (HDACi) have demonstrated antitumor potential in preclinical studies, none have been approved for breast cancer due to inconsistent efficacy across different subtypes. Panobinostat (LBH589), a pan-HDACi with favorable pharmacological properties, has shown clinical efficacy in multiple myeloma and other malignancies, but its role in breast cancer remains insufficiently studied.

METHODS AND RESULTS: In this study, the effects of LBH589 on triple-negative breast cancer (TNBC) were systematically investigated. Results revealed that LBH589 downregulated c-myc, disrupted the epithelial-mesenchymal transition (EMT) program, inhibited proliferation, migration, and invasion, and induced apoptosis. Moreover, LBH589 enhanced tumor immunogenicity by upregulating MHC I/II antigen presentation pathways, thereby promoting dendritic cell maturation. In vivo, LBH589 markedly induced tumor apoptosis and inhibited growth, accompanied by increased proportions of CD8+ T, CD4+ T, and NK cells. Serum cytokine analysis showed that LBH589 significantly increased the level of IFN-γ and decreased the levels of MCP-1, IL-1β, IL-17, and IL-10, indicating enhanced antitumor immunity and suppression of tumor-promoting factors.

CONCLUSION: Our study demonstrates that LBH589 not only directly induces apoptosis, inhibits proliferation, migration, and invasion, but also enhances the anti-tumor immune response through improving tumor immunogenicity. These findings not only broaden the mechanistic understanding of HDACi in TNBC, but also provide a theoretical basis for combining epigenetic therapy with immunotherapy, supporting LBH589 as a potential immunotherapy sensitizer for triple-negative breast cancer.