Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling

Abstract

BackgroundTriple-negative breast cancer (TNBC) has a high risk of relapse and there are few chemotherapy options. Although 5-hydroxytryptamine (5-HT, serotonin) signaling pathways have been suggested as potential targets for anti-cancer drug development, the mechanism responsible for the action of 5-HT in TNBC remains unknown.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to measure mRNA and protein levels, respectively. Cell proliferation was measured using CellTiter 96 Aqueous One Solution. siRNA transfection was used to assess involvement of genes in cancer invasion, which were identified by Matrigel transwell invasion assay. Levels of 5-HT and vascular endothelial growth factor (VEGF) were measured using ELISA kits. Chick chorioallantoic membrane (CAM) assay and mouse tumor model were used to investigate the in vivo effects of SB269970, a 5-HT7 receptor antagonist, and BJ-1113, a novel synthetic compound.ResultsTNBC cell lines (MDA-MB-231, HCC-1395, and Hs578T) expressed higher levels of tryptophan hydroxylase 1 (TPH1) than hormone-responsive breast cancer cell lines (MCF-7 and T47D). In MDA-MB-231 cells, 5-HT promoted invasion and proliferation via 5-HT7 receptor, and interestingly, the stimulatory effect of 5-HT on MDA-MB-231 cell invasion was stronger than its effect on proliferation. Likewise, downstream signaling pathways of 5-HT7 differed during invasion and proliferation, that is, Gα-activated cAMP and Gβγ-activated kinase signaling during invasion, and Gβγ-activated PI3K/Akt signaling during proliferation. Also, 5-HT increased the protein expressions of TPH1 and VEGF in MDA-MB-231 cells. These results provide insight of the stimulatory effect of 5-HT on breast cancer progression; 5-HT was found to act more strongly during the first stage of metastasis (during invasion and migration) than during the later proliferative phase after local invasion. Interestingly, these actions of 5-HT were inhibited by BJ-1113, a 6-amino-2,4,5-trimethylpyridin-3-ol analog. BJ-1113 blocked intracellular signaling pathways initiated by 5-HT7 receptor activation, and exhibited anti-proliferative and anti-invasive activities against MDA-MB-231 cells. Furthermore, the inhibitory effect of BJ-1113 against MDA-MB-231 tumor growth was greater than that of SB269970, a 5-HT7 receptor antagonist.Conclusions5-HT7 receptor which mediates 5-HT-induced cancer progression is a potential therapeutic target in TNBC, and BJ-1113 offers a novel scaffold for the development of anti-cancer agents against TNBC.

5‐Hydroxytryptamine Receptor 1D Aggravates Hepatocellular Carcinoma Progression Through FoxO6 in AKT‐Dependent and Independent Manners

“…The increased secretion of serotonin has been observed to have growth‐promoting effects on cholangiocarcinoma cells . In triple‐negative breast cancer, 5‐HT acts as a stimulator of cancer progression through a 5‐HT7 receptor–dependent signaling pathway . A positive relation between phosphatase and tensin homolog (PTEN) expression and serotonin secretion in carcinoid tumors has been demonstrated.…”

FOXF2 differentially regulates expression of metabolic genes in non-cancerous and cancerous breast epithelial cells

“…CYP1B1 has an oncogenic role in cancer due to its role in the metabolism of 17β-estradiol (E2) and E2-like molecules, which causes DNA adducts and generates free radicals leading to DNA damage and tumorigenesis in different tissues like breast [30]. Consistently, TPH1, an enzyme involved in serotonin (5-hydroxytryptamine or 5-HT) biosynthesis via catalyzing tryptophan metabolism, has been shown to be overexpressed in basal-like TNBC cell lines like MDA-MB-231 [31]. In line with this finding, 5-HT treatment promoted invasion and proliferation of MDA-MB-231 cells via 5-HT 7 receptor [31].…”

“…Consistently, TPH1, an enzyme involved in serotonin (5-hydroxytryptamine or 5-HT) biosynthesis via catalyzing tryptophan metabolism, has been shown to be overexpressed in basal-like TNBC cell lines like MDA-MB-231 [31]. In line with this finding, 5-HT treatment promoted invasion and proliferation of MDA-MB-231 cells via 5-HT 7 receptor [31]. These findings together imply that FOXF2 may also have a tumor-suppressive role in TNBC development via its negative regulation of CYP1B1 and TPH1.…”

The Impact of the Serotonin on the Cause and Treatment of Cancer

“…Furthermore, the inhibitory effect of BJ-1113 against MDA-MB-231 tumor growth was greater than that of SB269970, a 5HT receptor antagonist. 5-HT receptor which mediates 5-HT-induced cancer progression is a potential therapeutic target in TNBC, and BJ-1113 offers a novel scaffold for the development of anti-cancer agents against TNBC [51] .…”