Subtype-specific HER3 enrichment in basal-like breast cancer is regulated via the GATA2/GATA3–FOXA1 axis

Abstract

Basal-like breast cancer (BLBC) is a major subtype of triple-negative breast cancer (TNBC), characterized by aggressive behavior, limited treatment options, and poor prognosis. While HER3 overexpression is frequently observed in TNBC and associated with poor outcomes, its subtype-specific expression and therapeutic potential remain unclear. Here, we demonstrated that HER3 signaling is selectively hyperactivated in BLBC compared to claudin-low breast cancer (CLBC) using transcriptomic profiling. Histone deacetylase inhibitors (HDACi), Romidepsin and Panobinostat, exerted potent antitumor effects on BLBC by selectively downregulating HER3 expression. HER3 levels were positively correlated with FOXA1, a key transcriptional activator. Mechanistically, we identified GATA2 and GATA3 as upstream regulators of both FOXA1 and HER3. HDACi disrupted the GATA2/GATA3-FOXA1-HER3 axis by suppressing GATA2 and GATA3 expressions. Specific knockdown of FOXA1, GATA2, or GATA3 enhanced HDACi-induced apoptosis and growth inhibition, while ectopic expression of any of these transcription factors restored HER3 levels and mitigated the effects of HDACi. Chromatin immunoprecipitation assays confirmed direct binding of GATA2 and GATA3 to the FOXA1 promoter. In BLBC xenograft models, GATA2 overexpression markedly attenuated the antitumor activity of Panobinostat and substantially reversed its effects on FOXA1 and HER3 expression, tumor growth, and apoptosis. Clinically, high expression of GATA2, GATA3, FOXA1, or HER3 is significantly associated with poor outcomes in BLBC patients. Collectively, our studies established a previously unrecognized GATA2/GATA3-FOXA1-HER3 axis as a key regulatory network in BLBC progression. We provide strong experimental data supporting that the two HDACi, Romidepsin and Panobinostat may be repurposed as effective therapeutic agents for BLBC.