The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma

Abstract

Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2−ve tumors correlating with poor prognosis. However, there is no evidence, so far, of the functional contribution of AT1R to breast tumorigenesis. We explored the potential therapeutic benefit of ARB in a carcinogen-induced mouse model of breast cancer and clarified the mechanisms associated with its success.Mammary tumors were induced with 7,12-dimethylbenz[α]antracene (DMBA) and medroxyprogesterone acetate (MPA) in female wild type mice and the effects of the ARB, Losartan treatment assessed in a preventative setting (n = 15 per group). Tumor histopathology was characterised by immunohistochemistry, real-time qPCR to detect gene expression signatures, and tumor cytokine levels measured with quantitative bioplex assays. AT1R was detected with radiolabelled ligand binding assays in fresh frozen tumor samples.We showed that therapeutic inhibition of AT1R, with Losartan, resulted in a significant reduction in tumor burden; and no mammary tumor incidence in 20% of animals. We observed a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This was associated with reduced tumor cell proliferation and a significant reduction in IL-6, pSTAT3 and TNFα levels. Analysis of tumor immune cell infiltrates, however, demonstrated no significant differences in the recruitment of lymphocytes or tumour-associated macrophages in Losartan or vehicle-treated mammary tumors.Analysis of AT1R expression with radiolabelled ligand binding assays in human breast cancer biopsies showed high AT1R levels in 30% of invasive ductal carcinomas analysed. Furthermore, analysis of the TCGA database identified that high AT1R expression to be associated with luminal breast cancer subtype.Our in vivo data and analysis of human invasive ductal carcinoma samples identify the AT1R is a potential therapeutic target in breast cancer, with the availability of a range of well-tolerated inhibitors currently used in clinics. We describe a novel signalling pathway critical in breast tumorigenesis, that may provide new therapeutic avenues to complement current treatments.

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

“…Immunohistochemistry was performed using antibodies directed against pSTAT3, Ki67, and b-catenin as previously published (Putoczki et al, 2013;Phesse et al, 2014;Coulson et al, 2017). 4lm-thick sections from paraffin blocks were re-hydrated, antigen retrieval performed with citrate buffer (0.1%) by microwaving for 15 min.…”

Why isn’t the angiotensin type 1 receptor a target in cancer?

“…The clear in-vivo effects of AT1R blockers shown in animal cancers by various authors, and now amply confirmed by Coulson et al [1], have all been obtained using very high doses. In their paper, mice received 70mg losartan/kg/day, compared with the normal range of 20-100mg per day for adult patients.…”

“…The paper by Coulson et al [1] provides some of the most comprehensive evidence to date that an angiotensin type 1 receptor blocker, losartan, has highly beneficial effects on mammary tumor development and progression to invasive carcinoma in experimental animals.…”

“…These data of course are from patients receiving drugs for reasons other than cancer, and do not necessarily predict the outcome of any clinical trial in which they are used for cancer treatment. When combined with anti-cancer therapy, as in the studies cited by Coulson et al [1], RAS blockade has been shown to bring significant benefit.…”

The potential actions of angiotensin‐converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases

“…The RAS also plays a role in cancer, for example, Ang II has been shown to promote adhesion, proliferation, migration and angiogenesis resulting in the development of an array of varying cancers . Several studies have linked the presence and more specifically the upregulation of AGTR1 (the gene that codes the AT1 R) to the pathogenesis of certain cancers, particularly invasive breast carcinoma . Studies have also linked ACE2 expression and its potential mechanism in numerous cancer cells and tissues by counter regulating ACE activity .…”