Abstract 5213: HRH1 inhibition enhances antitumor therapeutic responses through ERK activation in breast cancer

Abstract

Abstract Histamine receptor 1 (HRH1) belongs to the rhodopsin-like G-protein-coupled receptor family. Its activation by histamine, a ubiquitous messenger molecule released mostly from mast cells, has been demonstrated to be involved in cell proliferation, embryonic development, and tumor growth. In particular, high levels of HRH1 have been associated with dual behavior in the regulation of several tumors. Most of the physiological and pathological actions of HRH1 have been shown to depend strictly on its level of expression and the tumor cell type under study. We recently established that HRH1 is upregulated in patients with basal and HER2-enriched breast tumors and that its expression correlates with a worse prognosis. Despite this, the functional role of HRH1 basal and HER2 targeted therapies for resistant breast cancer (BC) progression has not so far been addressed. We assessed HRH1 expression in a wide panel of breast cancer cell lines and found HRH1 overexpressed in basal and HER2-targeted therapy resistant to BC cell lines at the protein and mRNA levels, corroborating data previously published using patient databases. Using terfenadine, a selective chemical inhibitor of HRH1, we showed that inhibition of HRH1 activity in basal BC cells leads to sub-G0 accumulation, suppresses proliferation, promotes cell motility and triggers the activation of ERK signaling, initiating the mitochondrial pathway of caspase cascade activation, inducing apoptosis. Moreover, in vivo experiments showed that terfenadine therapy reduced basal and HER2-targeted therapies for resistant BC cell tumor growth but does not affect luminal and parental tumor growth. In conclusion, our results suggest that targeting HRH1 might be an effective therapeutic treatment in patients with basal and HER2-targeted resistant BC tumors. Citation Format: Patricia Fernandez-Nogueira, Aleix Noguera Castells, Gemma Fuster Orellana, Leire Recalde Percaz, Nuria Moragas Garcia, Anna Lopez Plana, Patricia Jauregui Jimenez, Maria Neus Carbó Carbó, Pedro Gascon Villaplana, Paloma Bragado Domingo, Mario Mancino. HRH1 inhibition enhances antitumor therapeutic responses through ERK activation in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5213.