Angiotensin II type 1 receptor antagonists inhibit cell proliferation and angiogenesis in breast cancer

Purpose: To evaluate the association between angiotensin receptor blocker (ARB) usage and breast cancer characteristics and outcomes. Methods: All patients who were treated in our institute for estrogen receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer between April 2005 and March 2012 and whose tumors were sent for Oncotype-DX analysis were included. Medical records were retrospectively reviewed. Data regarding ARB usage were retrieved. Usage of several prespecified medications for hypertension was also evaluated. Each medication group was compared with the rest of the cohort. Results: A total of 671 patients were included. Forty-six (7%) patients were treated with ARB. ARB usage was associated with macroscopic nodal involvement (p < 0.001) and a more advanced stage at diagnosis (p < 0.001). These findings remained significant in the multivariate analysis. Patients treated with ARB also had a higher incidence of invasive lobular carcinoma subtype (p = 0.009), a worse 5-year breast cancer-specific survival (94.7 vs. 98.8%, p = 0.024) and a worse 5-year overall survival (94.6 vs. 98.8%, p = 0.015), but these differences were not demonstrated in the multivariate analysis. Conclusions: Patients treated with ARB presented with a more advanced breast cancer disease and some distinct histological features. Further research is required to elucidate the effect of ARB treatment on breast cancer.

show abstract

“…These findings may support the theory that ARB could have a role in the pathophysiology of breast cancer development [13,35]. …”

Section: Discussionsupporting

confidence: 85%

The Association between Angiotensin Receptor Blocker Usage and Breast Cancer Characteristics

Goldvaser¹,

Rizel²,

Hendler³

et al. 2016

Oncology

View full text Add to dashboard Cite

show abstract

“…And now the AGTR1 blocker has been applied in the clinical oncology, such as the losartan for breast cancer (22) and candesartan for prostate cancer (23). And now emerging evidences showed that AGTR1 regulates the cell proliferation during cancer development, and promotes tumor invasion, migration, metastasis and angiogenesis (24). In consideration of the unfavorable treatment status of NSCLC, detection of biomarkers like the AGTR1 is really necessary and urgent.…”

Section: Discussionmentioning

confidence: 99%

AGTR1 promoter hypermethylation in lung squamous cell carcinoma but not in lung adenocarcinoma

et al. 2017

View full text Add to dashboard Cite

Abstract. Aberrant DNA methylation is associated with non-small cell lung cancer (NSCLC), suggesting that gene promoter methylation may be a potential biomarker for the detection or risk prediction of NSCLC. The present study aimed to evaluate the potential usage of angiotensin II receptor type 1 (AGTR1) methylation in two major pathologic subtypes: Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Quantitative methylation-specific polymerase chain reaction was used to investigate the effect of AGTR1 promoter methylation in the tumor and the paired adjacent non-tumor tissue samples from 42 patients with LUSC, and 69 with LUAD. The percentage of methylated reference was calculated and presented as the median (interquartile range 25th-75th percentile). The results of the current study revealed that there was significantly increased AGTR1 promoter methylation in the tumor tissues compared with the paired adjacent non-tumor tissue [97.4 (57.22-130.5) vs. 85 (48.25-123); P=0.024]. Furthermore, higher AGTR1 promoter methylation was observed in patients with LUSC compared with LUAD (odds ratio=2.483; 95% confidence interval=1.125-5.480; P=0.023). Significant differences were identified in AGTR1 methylation between non-tumor and the tumor tissues in LUSC [113.5 (68.33-148.73) vs. 93.04 (45.94-140); P=0.008]. In addition, the Cancer Genome Atlas data of 378 patients with LUSC and 477 with LUAD revealed an inverse correlation between gene expression and the methylation status of AGTR1 promoter.. These data suggest that AGTR1 hypermethylation is a promising biomarker to assist in LUSC detection and diagnosis. IntroductionLung cancer is a kind of malignancy that arises from epithelial cells. It is the leading cause of cancer-related death worldwide (1). There were nearly 1.8 million new patients and caused 159 million deaths in 2012, of which China accounted for more than one third (2). According to the size and appearance of the malignant cells, lung cancer is categorized as non small cell lung cancer (NSCLC) and small cell lung cancer (3). NSCLC represents approximately 85% of lung cancer (4), and it can be further subdivided into large cell carcinoma, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). There are a lot of differences in molecular profiling, characteristics and therapeutic methods between LUAD and LUSC (5).Promoter hypermethylation of the tumor suppressor genes has been recognized as an important factor in inducing oncogenesis (6). For example, SRY-box 17 (SOX17) methylation was found in 60.2% of primary lung cancer samples, and promoter methylation of SOX17 silenced gene expression, leading to the elimination of cell proliferation suppression in lung cancer (7). Identification of specific gene hypermethylation may explain the genomic instability and complexity of NSCLC and provide a basis for targeted therapy or risk prediction. AGTR1 promoter hypermethylation in lung squamouscell carcinoma but not in lung adenocarcinoma

show abstract

“…The effects of ARBs on angiogenesis are debated and are likely to be dose-, tissue-, and context-dependent (Willis et al, 2011). Candesartan and other AT1 blockers have been demonstrated to inhibit the proliferation of cancer cells when used alone or in combination with other antineoplastic agents (Fujimoto et al, 2001;Miyajima et al, 2002;Kosugi et al, 2006;Kosaka et al, 2007;Chen et al, 2013). This antiproliferative effect was observed with high doses of AT1 blockers that are not clinically relevant and may have serious side effects, such as hypotension and kidney failure.…”

Section: Discussionmentioning

confidence: 99%

“…This point has been critically reviewed, and the importance of using clinically relevant doses of pharmacologic agents in preclinical studies has been noted (Reagan-Shaw et al, 2008). Another important consideration in investigating the effects of ARBs is the concomitant treatment with exogenous AngII (Uemura et al, 2003;Kosaka et al, 2007;Chen et al, 2013), which only blunted AngII-mediated effects. This paradigm ignores AngII-independent effects of candesartan as well as the role of locally produced AngII, which has been well characterized in a variety of tissues and cell types (Reid et al, 2011;Angeli et al, 2013;Lu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Clinically Relevant Doses of Candesartan Inhibit Growth of Prostate Tumor Xenografts In Vivo through Modulation of Tumor Angiogenesis

Alhusban

Al-Azayzih

Goc

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Angiotensin II receptor type 1 blockers (ARBs), widely used antihypertensive drugs, have also been investigated for their anticancer effects. The effect of ARBs on prostate cancer in experimental models compared with meta-analysis data from clinical trials is conflicting. Whereas this discrepancy might be due to the use of supratherapeutic doses of ARBs in cellular and animal models as compared with the clinical doses used in human trials, further investigation of the effects of clinical doses of ARBs on prostate cancer in experimental models is warranted. In the current study, we sought to determine the effects of candesartan on prostate cancer cellular function in vitro and tumor growth in vivo, and characterize the underlying mechanisms. Our analysis indicated that clinically relevant doses of candesartan significantly inhibited growth of PC3 cell tumor xenografts in mice.Interestingly, the same concentrations of candesartan actually promoted prostate cancer cellular function in vitro, through a modest but significant inhibition in apoptosis. Inhibition of tumor growth by candesartan was associated with a decrease in vascular endothelial growth factor (VEGF) expression in tumors and inhibition of tumor angiogenesis, but normalization of tumor vasculature. Although candesartan did not impair PC3 cell viability, it inhibited endothelialbarrier disruption by tumor-derived factors. Furthermore, candesartan significantly inhibited expression of VEGF in PC3 and DU145 cell lines independent of angiotensin II type 2 receptor, but potentially via angiotensin II type 1 receptor inhibition. Our findings clearly demonstrate the therapeutic potential of candesartan for prostate cancer and establish a link between ARBs, VEGF expression, and prostate tumor angiogenesis.

show abstract

Angiotensin II type 1 receptor antagonists inhibit cell proliferation and angiogenesis in breast cancer

Cited by 98 publications

References 23 publications

The Association between Angiotensin Receptor Blocker Usage and Breast Cancer Characteristics

The Association between Angiotensin Receptor Blocker Usage and Breast Cancer Characteristics

AGTR1 promoter hypermethylation in lung squamous cell carcinoma but not in lung adenocarcinoma

Clinically Relevant Doses of Candesartan Inhibit Growth of Prostate Tumor Xenografts In Vivo through Modulation of Tumor Angiogenesis

Contact Info

Product

Resources

About