angiotensinogen and Breast-Neoplasms

The renin-angiotensin system (RAS) has been considered to be implicated in the development of breast cancer. However, the results are inconsistent. In this study, we conducted a meta-analysis to assess the association between four polymorphisms, including angiotensin I-converting enzyme (ACE) I/D and A240T, angiotensin II type 1 receptor (AGTR1) A1166C and angiotensinogen (AGT) M235T polymorphisms, and breast cancer risk. Published literature from PubMed, ISI web of science, and Embase databases were retrieved. All studies evaluating the association between ACE I/D, ACE A240T, AGTR1 A1166C, or AGT M235T polymorphism and breast cancer risk were included. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Ten studies (1,650 cases and 9,283 controls) on ACE I/D polymorphism, six studies (1,316 cases and 2,632 controls) on ACE A240T polymorphism, three studies (235 cases and 601 controls) on AGTR1 A1166C polymorphism, and two studies (273 cases and 3,547 controls) on AGT M235T polymorphism were included. Overall, the meta-analysis showed no significant association between I/D or A240T polymorphism and breast cancer risk in either genetic model. Further subgroup analysis by ethnicity also revealed non-significant association in Caucasian or Asian populations except for Africans (the statistically significant association for ACE I/D or A240T polymorphism in Africans derived from only one study). A marginally significant association was observed for AGTR1 A1166C polymorphism in Caucasians (CC vs. AA: OR = 0.31, 95% CI 0.10-0.99). In addition, there was a significant association between AGT M235T polymorphism and breast cancer risk in Caucasians (OR = 1.45, 95% CI 1.12-1.88). The present meta-analysis suggested that ACE I/D and A240T polymorphisms might not be a good predictor of breast cancer risk, while AGTR1 A1166C and AGT M235T polymorphisms might be implicated in the pathogenesis of breast cancer. Given the limited sample size, the findings warrant further investigation.

Topics: Angiotensinogen; Breast Neoplasms; Case-Control Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; INDEL Mutation; Models, Genetic; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors

The tissue renin-angiotensin system (RAS) plays an important role in the development and progression of many diseases. It has been confirmed that angiotensin II (ANG II) participates in the proliferation and angiogenesis of breast cancer. Moreover, some RAS dysregulations in cancer have been observed. Recent studies on the role of two opposite axes of angiotensinogen metabolism - ACE (angiotensin-converting enzyme)/ANGII/AT1R (angiotensin receptor type 1) and ACE-2/ANG 1-7/MAS (mitochondrial assembly) - indicate their importance in tumor growth and invasion, but studies describing the metabolic pathways in breast cancer and the role of newer angiotensins, such as ANG 1-12, remain lacking. In this study, the metabolism of angiotensinogen fragments in three breast cancer lines, namely, MDA-MB-231, MCF-7, and T-47D, compared with normal breast tissue cells (PCS-600) was estimated. Incubation of the cancer cells with angiotensinogen resulted in the prevalent formation of ANG 1-7. A difference in the ability to form ANG II was observed between cell lines. In normal breast cells, the strong predominance of the ACE-2/ANG 1-7/MAS pathway was detected. In cancer cells, differences in angiotensinogen metabolism depending on cancer line were observed; the prevalence of the ACE/ANG II/AT1R pathway was shown. Expressions of the RAS component were dysregulated in cancer cells and differed between cell lines. In conclusion, the ability of breast cancer cells to produce numerous angiotensin peptide metabolites was demonstrated. The metabolism of angiotensinogen differed between various types of breast cancer cells. The obtained results indicate the greater importance of the classical pathway - ACE/ANG II/AT1R - in breast cancer cells. The production of ANG 1-12 seems to be marginal in breast tissue, but a tendency for the higher formation of this peptide in cancer cells was observed. The production of ANG 1-7 was significantly lower in cancer cells, whereas the expression of MAS receptor was higher than that in the control. This finding suggests that substances with MAS receptor agonist activity could be useful in the treatment of breast cancer, but this requires further investigations.

Topics: Angiotensin I; Angiotensinogen; Breast; Breast Neoplasms; Cell Line; Female; Humans; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled

A number of investigations have addressed the importance of high glucose in breast cancer, however, the involvement of angiotensinogen (AGT) in this scenario is yet to be defined. Here we set out to analyze the potential pro-tumor effects of high glucose in breast cancer, and understand the underlying molecular mechanism. We demonstrated that high glucose promoted cell proliferation, viability, and anchorage-independent growth of breast cancer cells. In addition, the migrative and invasive capacities were significantly enhanced by high glucose medium. Mechanistically, AGT expression was inhibited by high glucose at both transcriptional and translational levels. High AGT remarkably suppressed proliferation, inhibited viability, and compromised migration/invasion of breast cancer cells. Most importantly, ectopic introduction of AGT almost completely abrogated pro-tumor effects of high glucose. Our study has characterized the pro-tumor properties of high glucose in breast cancer cells, which is predominantly attributed to the suppression of AGT.

Topics: Angiotensinogen; Breast Neoplasms; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Glucose; Humans; MCF-7 Cells; Neoplasm Metastasis; Neoplasm Proteins

Breast cancer is the most common malignancy that is believed to be largely under genetic control. We therefore investigated both individual and interactive associations of six well-characterized polymorphisms in three genes of the renin-angiotensin system with breast cancer among Han Chinese women.. This was a hospital-based study involving 606 patients diagnosed with sporadic breast cancer and 633 age- and ethnicity-matched controls. There were significant differences in genotype and allele distributions of ACE gene rs4343 (pgentoype = 0.002 and pallele < 0.001) and AGTR1 gene rs5186 polymorphisms (pgentoype < 0.001 and pallele < 0.001), even with a Bonferroni-corrected alpha of 0.0042 (0.05/12). Allele combinations of T-T-T-G-C-A (alleles in order of rs5050, rs699, rs4291, rs4343, rs188018 and rs5186), G-C-T-G-C-A and T-C-T-G-C-C, respectively, had the age-adjusted odds of 2.21 (p = 0.021), 3.01 (p = 0.021) and 5.24 (p = 0.015) for breast cancer, whereas allele combination T-C-T-A-T-A was associated with a 76% (p = 0.008) reduced risk. Interaction analysis revealed an overall best two-locus model including rs4343 and rs4291 polymorphisms, and this model had the maximal testing accuracy of 0.6259 with a cross-validation consistency of 10 (p = 0.0015).. Our findings support a contributory role of the ACE gene, with its genetic polymorphisms acting synergistically, in predisposition to breast cancer among Han Chinese women.

Topics: Alleles; Angiotensinogen; Asian People; Breast Neoplasms; Case-Control Studies; Epistasis, Genetic; Ethnicity; Female; Gene Frequency; Genetic Loci; Genetic Predisposition to Disease; Humans; Middle Aged; Models, Genetic; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors

Breast cancer (BC) is one of the most common cancer pathologies in women. Genetic polymorphism of genes of renin-angiotensin system (RAS) is considered to be associated with cancer development, in particular, with BC.. To study the influence of polymorphic variants of genes coding for RAS components, on the risk of BC development in Ukrainian women.. In the study 131 patients with histologically proven diagnosis of BC of I and II stages were enrolled. The control group was composed from 102 women without cancer. Polymorphic variants of AGT, ACE, AT2R1 genes were studied with the use of PCR and PCR-RFLP methods.. It has been revealed that the presence of 1166АС genotype of AT2R1 gene elevates the risk of BC development nearly 2-fold. The results of analysis for common group and subgroups distributed by age are different. For women from 18 to 35 years old the significant differences were not found. For women from 36 to 54 years old an increased risk of BC development is determined by the presence of D allele of АСЕ gene. Decreased risk of BC development was associated with the presence of combined genotypes ACE II/AGT 174TT and ACE II/AGT 235МТ. In women older than 54 years an increased risk of BC development was found to be related to the presence of genotypes 235ТT of AGT gene and 1166АС of AT2R1 gene. The presence of genotype combinations AGT 235ТТ/AGT 174ТМ and AGT 235ТТ/AT2R1 1166AA in women of this age subgroup also significantly increases the risk of BC development.. These polymorphic gene variants and their associations may be considered as possible prognostic markers of BC development. The results of analysis are different in total cohort and in subgroups distributed by age.

Topics: Adult; Aged; Angiotensinogen; Breast Neoplasms; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Ukraine; Young Adult

Anthracyclines are among the most active drugs against breast cancer, but can exert cardiotoxic effects eventually resulting in congestive heart failure (CHF). Identifying breast cancer patients at high risk of developing cardiotoxicity after anthracycline therapy would be of value in guiding the use of these agents.. We determined whether polymorphisms in the renin-angiotensin-aldosterone system (RAAS) and in the glutathione S-transferase (GST) family of phase II detoxification enzymes might be useful predictors of left ventricular ejection fraction (LVEF) kinetics and risk of developing CHF. We sought correlations between the development of cardiotoxicity and gene polymorphisms in 48 patients with early breast cancer treated with adjuvant anthracycline chemotherapy.. We analyzed the following polymorphisms: p.Met235Thr and p.Thr174Met in angiotensinogen (AGT), Ins/Del in angiotensin-converting enzyme (ACE), A1166C in angiotensin II type-1 receptor (AGTR1A), c.-344T>C in aldosterone synthase (CYP11B2), p.Ile105Val in GSTP1. Additionally, we analyzed the presence or absence of the GSTT1 and GSTP1 genes. A LVEF <50% was detected at least once during the 3 years of follow-up period in 13 out of 48 patients (27.1%).. RAAS gene polymorphisms were not significantly associated with the development of cardiotoxicity. GSTM1may be useful as a biomarker of higher risk of cardiotoxicity, as demonstrated in our cohort of patients (p=0.147).

Topics: Adult; Aged; Angiotensinogen; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Breast Neoplasms, Male; Chemotherapy, Adjuvant; Cyclophosphamide; Epirubicin; Female; Fluorouracil; Glutathione Transferase; Heart Diseases; Humans; Isoenzymes; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Renin-Angiotensin System

While angiotensinogen (AGT) seems to have anti proliferative properties, angiotensin II (ATII) is a potent growth factor and it mediates its actions through the angiotensin type 1 receptor (AGTR1). In the AGT gene, the M235T polymorphism has been associated with the variation in angiotensinogen levels and in the AGTR1 gene; the C573T variant is associated with different pathologies. We aimed to evaluate the relationship of these two variants and the risk of breast cancer. These polymorphisms were genotyped in 3787 women participating the Rotterdam Study. We performed a logistic regression and a disease free survival analysis by genotype. The logistic regression yielded an odds ratio of 1.4 (95% CI: 1.1-1.9) for the MM genotype carriers versus the T allele carriers. The breast cancer free survival by AGT genotype was significantly reduced in MM genotype carriers compared to non-carriers (hazard ratio (HR) = 1.5; 95% CI: 1.1-2.2). We did not find any association of the AGTR1 polymorphism and breast cancer risk or disease free survival. Our results suggest that AGT plays a role in breast cancer risk in postmenopausal women, whereas the role of AGTR1 needs further studying.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Body Mass Index; Breast Neoplasms; Case-Control Studies; Disease-Free Survival; DNA; DNA Mutational Analysis; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Middle Aged; Netherlands; Polymorphism, Single Nucleotide; Prevalence; Receptor, Angiotensin, Type 1; Risk Factors

Angiotensin II has mitogenic and angiogenic effects and its receptors are widespread, particularly in epithelial tissue. Tissue renin angiotensin systems (tRASs) may be a local source of angiotensin II that has specific paracrine functions. To investigate the presence of a tRAS in normal human breast and tumours. Immunocytochemistry, and quantitative RT-PCR was used to establish: (i) the presence and localisation of RAS components, (ii) the possibility of their involvement in cancer. (1) mRNA coding for angiotensinogen, prorenin, angiotensin converting enzyme (ACE), and both AT1 and AT2 receptors was demonstrated in normal and diseased breast tissues. (2) (pro)renin was identified in epithelial cells in both normal and diseased tissue, but in invasive carcinoma, its distribution was mostly confined to fibroblasts or could not be detected at all. (3) Angiotensin converting enzyme was shown in epithelial cells in both normal and malignant tissue. The results are consistent with the hypothesis that a tRAS is present in the breast, and is disrupted in invasive cancer.

Topics: Angiotensin II; Angiotensinogen; Breast Neoplasms; Female; Gene Expression Profiling; Humans; Immunohistochemistry; Mammary Glands, Human; Neoplasm Invasiveness; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger