HER3 promotes triple-negative breast cancer progression by upregulating PHF8 via miR-34b-5p-dependent mechanism

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with limited targeted treatment options and poor clinical outcomes. HER3 has recently emerged as a promising therapeutic target, with HER3-directed antibody-drug conjugates advancing to Phase III clinical trials for non-small cell lung cancer. However, the downstream molecular mechanisms by which HER3 promotes TNBC progression remain poorly defined. In this study, we uncovered a previously unrecognized HER3/miR-34b-5p/PHF8 signaling axis that drives TNBC cell proliferation and tumor growth. Mechanistically, HER3 activation suppresses the tumor-suppressive microRNA miR-34b-5p, resulting in the upregulation of the histone demethylase PHF8 (KDM7B), which in turn represses the expression of the CDK inhibitor p27^Kip1 and facilitates G1-S cell cycle progression. Functional studies using shRNA-mediated knockdown and overexpression systems demonstrate that PHF8 is a critical downstream effector of HER3. PHF8 depletion phenocopied HER3 knockdown, inducing G1 arrest and suppressing colony formation and proliferation in multiple TNBC cell lines, while PHF8 overexpression rescued the inhibitory effects of HER3 loss. Furthermore, orthotopic xenograft models revealed that enforced PHF8 expression restored tumor growth suppressed by HER3 silencing in vivo. Clinically, HER3 and PHF8 expression levels were positively correlated in TNBC tissue specimens, and TCGA dataset analyses indicated that the HER3/miR-34b-5p/PHF8 axis is significantly associated with poor survival outcomes in breast cancer patients. Collectively, our findings establish a novel epigenetic regulatory circuit through which HER3 drives TNBC progression and lay the groundwork for future therapeutic strategies aimed at disrupting HER3-epigenetic crosstalk in TNBC.