Abstract 2969: Histone deacetylase (HDAC) inhibitors exhibit antitumor activity in triple negative breast cancer via suppression of HER3 triggered signaling

Abstract

Abstract Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high rate of recurrence and refractoriness due to lack of well-defined molecular targets. Human epidermal growth factor receptor 3 (HER3) is differentially expressed in TNBC cells. Numerous studies indicate that elevated expression of HER3, through its dimerization with another receptor, is a major cause of treatment failure in human cancers. To date, there is no FDA-approved HER3-targeted cancer therapy. HDAC inhibitors (HDACis) have been approved for the treatment of refractory or relapsed cutaneous T cell lymphomas and show potency in TNBC cells. However, it remains unclear whether the HDACis may alter HER3 expression to influence the downstream signaling in HER3-overexpressing (HER3high) TNBC. Methods: Colony formation, MTS and LIVE/DEAD cell staining assays were used to detect cell viability. Apoptosis was detected by flow cytometry assays. QRT-PCR, western blots and immunohistochemistry were performed to determine the expression and activation of genes and/or proteins. Co-immunoprecipitation was performed to assess the interaction between proteins. Lentivirus vectors containing cDNA or shRNAs were used to overexpress or knockdown gene expression. Chromatin immunoprecipitation-quantitative PCR and dual luciferase reporter assays were performed to elucidate the regulatory role of gene transcription. Results: Elevated expression of HER3 were observed in approximately half of the TNBC specimens and cell lines tested. HER3 was co-expressed and formed heterodimers with epidermal growth factor receptor (EGFR) to activate the PI-3K/Akt signaling in HER3high-TNBC cells. Panobinostat and romidepsin induced growth inhibition and apoptosis in HER3high-TNBC cells via downregulating HER3 expression and inhibiting PI-3K/Akt signaling. Significantly, HDACis in combination with an EGFR inhibitor (gefitinib) or an Akt inhibitor (Akti1/2) synergistically enhanced the anti-survival effects on HER3high-TNBC cells. Besides, analyses of gene expression profiling datasets revealed a significantly positive correlation between expression of HER3 and transcription factor forkhead box A1 (FOXA1). Further studies discovered that FOXA1 activated HER3 expression through directly binding to HER3 promoter. Moreover, ectopic expression of FOXA1 not only rescued the expression of HER3-downregulated by HDACis, but also attenuated these HDACis-mediated anti-survival effects on HER3high-TNBC cells. Conclusion: HDAC inhibitors exhibits potent inhibitory effects on HER3high-TNBC cells via downregulation of FOXA1-mediated repression of HER3 gene transcription. Our data suggest that epigenetic targeting of FOXA1-HER3/EGFR-PI-3K/Akt signaling axis may be an effective therapeutic strategy for eradication of HER3high-TNBC tumors. Citation Format: Congcong Tan, Hui Lyu, sanbao Ruan, bolin Liu. Histone deacetylase (HDAC) inhibitors exhibit antitumor activity in triple negative breast cancer via suppression of HER3 triggered signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2969.