Abstract B100: Subtype specific expression of HRH1 contributes to increased chemoresistance of breast cancer cells

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Abstract Background: Histamine is a monoamine produced by α-decarboxylation of histidine by the enzyme histidine decarboxylase (HDC). Histamine acts as an autocrine regulator of cell proliferation through its binding to HRH1-4 receptors. In breast cancer (BC), there are controversial results about the therapeutic efficacy of HRH1 or HRH2 inhibitors and the role of histamine receptors in tumor progression. Given the phenotypic heterogeneity of BC and the presence of different molecular subtypes with different clinical outcome, we aimed to investigate the contribution of histamine receptors in the proliferation, migration and cell survival of BC cells of different molecular subtypes. Methods: The expression of histamine receptors HRH1-4 and HDC in human breast tumors of different subtypes, and their correlation with clinical variables were gathered through informatics analysis using the “Gene expression based Outcome for Breast cancer Online” (GOBO) web-based tool. The measurement of the mRNA levels of HRH1-4 and HDC in a panel of breast cancer cell lines was used to confirm the subtype specific expression of each protein. Using specific HRH inhibitors in luminal and basal-like breast cancer cell lines we assessed the functional role of histamine receptors in cell proliferation, migration and survival. Results: HRH1 was highly expressed in ER+ tumors while HDC was highly expressed in the ER- tumors. In any case, the high expression of HRH1 or HDC was significantly correlated with lower overall survival only in ER+ tumors. The same pattern of expression was observed in BC cell lines, where HRH1 was highly expressed in basal-like BC cells compared to the luminal ones. HRH2 and HRH3 were highly expressed in the estrogen-dependent MCF7 cell line, while HRH4 was not detected in any breast cancer cell line. Only the antagonism of HRH1 induced apoptosis, and decreased proliferation and migration, while HRH2 or HRH3 inhibition had no effect on cell survival. Interestingly, the luminal cell lines were more sensitive than the basal-like cell lines to HRH1 antagonism, even though the low expression of HRH1 in these cells. Conclusion: Taken together, these findings suggest a complex role of the autocrine histamine signaling system in the progression of BC tumors of different subtype through the activation of HRH1. Citation Format: Mario Mancino, Patricia Fernandez-Nogueira, Estel Enreig, Elisabet Ametller, Pedro Gascón, Vanessa Almendro. Subtype specific expression of HRH1 contributes to increased chemoresistance of breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B100.