ABSTRACT
Histamine H2 receptor (HRH2) was previously suggested to affect the proliferation of breast cancer cells and disease-free survival of breast cancer patients. Furthermore, a common polymorphism, rs2067474, was identified in an enhancer element of the HRH2 gene promoter and was reported to be associated with various diseases including cancer. However, the relationship between this polymorphism and breast cancer risk and malignant degree remains unclear. The aim of this study was to clarify the clinical association of rs2067474 polymorphism with breast cancer. A total of 201 unrelated Chinese Han breast cancer patients and 238 ethnicity-matched health controls were recruited and rs2067474 polymorphism was genotyped. Logistic regression analyses were performed to calculate the odds ratios (ORs) as a measure of association of genotype with breast cancer according to 3 genetic models (dominant, recessive, and additive). Although the percentage of hormone receptor negative cases tended to be higher in AA genotypes, we did not find any significant associations of rs2067474 polymorphism with breast cancer risk or with related clinicopathological parameters in the present study, which indicates that rs2067474 polymorphism of HRH2 gene might not be a risk factor in the development of breast cancer in Chinese Han population.
Subject(s)
Asian People/genetics , Breast Neoplasms/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Receptors, Histamine H2/genetics , Adult , Alleles , Biomarkers, Tumor , Breast Neoplasms/pathology , Case-Control Studies , China , Female , Gene Frequency , Genotype , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Staging , Risk FactorsABSTRACT
We previously found that genetic polymorphisms in gene coding for histamine H4 receptors were related to the risk and malignant degree of breast cancer. The roles of polymorphisms in other histamine-related genes, such as histidine decarboxylase (HDC), histamine N-methyltransferase (HNMT) and histamine H3 receptor (HRH3), remain unexplored. The aim of this study is to analyze the clinical associations of polymorphisms in HDC, HNMT and HRH3 with breast cancer. Two hundred and one unrelated Chinese Han breast cancer patients and 205 ethnicity-matched health controls were recruited for case-control investigation. Genomic DNA from the participants was extracted and 5 single nucleotide polymorphisms (SNPs) in HDC, HNMT and HRH3 were genotyped. We found that polymorphisms of HNMT and HRH3 were irrelevant with breast cancer in the present study. However, the T allele of rs7164386 in HDC significantly decreased the risk of breast cancer (adjusted odds ratios [ORs], 0.387; 95% confidence intervals [CIs], 0.208-0.720; Pâ=â0.003). Furthermore, for HDC haplotypes, the CG haplotype of rs7164386-rs7182203 was more frequent among breast cancer patients (adjusted OR, 1.828; 95% CI, 1.218-2.744; Pâ=â0.004) while the TG haplotype was more frequent among health controls (adjusted OR, 0.351; 95% CI, 0.182-0.678; Pâ=â0.002). These findings indicated that polymorphisms of HDC gene were significantly associated with breast cancer in Chinese Han population and may be novel diagnostic or therapeutic targets for breast cancer. Further studies with larger participants worldwide are still needed for conclusion validation.
Subject(s)
Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/genetics , Genetic Association Studies , Histamine N-Methyltransferase/genetics , Histidine Decarboxylase/genetics , Polymorphism, Single Nucleotide , Receptors, Histamine H3/genetics , Adult , Alleles , Breast Neoplasms/physiopathology , Carcinoma, Ductal, Breast/physiopathology , China , Female , Genetic Predisposition to Disease , Genotype , Humans , Middle AgedABSTRACT
Previous investigations found that epithelial-to-mesenchymal transition (EMT) was an important character of non-small cell lung cancer (NSCLC) and it was also suggested that histamine H4 receptors may have a role in preventing EMT progress in certain kind of tumours. However, the effect of H4 receptor activation on EMT progress of NSCLC and its potential mechanisms remain unclear. Therefore, we performed both in vitro and in vivo experiments to explore the effects of specific H4 receptor agonist 4-methylhistamine and antagonist JNJ7777120 on EMT progress. We showed the expression of H4 receptors in NSCLC and found that 4-methylhistamine increased the expression of the epithelial marker E-cadherin and decreased the expression of Vimentin, the mesenchymal marker, in both NSCLC cell lines and xenograft NSCLC tumours. Pretreatment with JNJ7777120 or H4 receptor gene silencing decreased while overexpression of H4 receptors facilitated this effect of 4-methylhistamine. Furthermore, we showed that down-regulation of cyclic adenosine monophosphate (cAMP) was the secondary signalling after H4 receptor activation, which in turn resulted in inactivation of transforming growth factor-ß1 (TGF-ß1) pathway and down-regulation of several important EMT inducing factors such as ZEB1, Snail and Slug. In conclusion, these findings revealed the anti-EMT effect of histamine H4 receptor activation in NSCLC, which provide novel insight into the development mechanism of NSCLC; and H4 receptors may be a new therapeutic target for NSCLC treatment.
