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.
Highlights
Breast cancer is the most frequently diagnosed cancer in women, with an estimated 1.38 million new cases per year [1]
Losartan treatment inhibits mammary tumour formation and progression in vivo Given that postmenopausal women account for ~70% of all breast cancer cases, and are more likely to be treated with Angiotensin Receptor Blockers (ARB) for hypertension, we wanted to elucidate the effects of prophylactic ARB treatment on breast cancer development and progression in vivo
Tumor cell proliferation, quantified by Ki67 immunostaining, was decreased in Losartan-treated animals (Figure 1c, P < 0.05), no significant changes were observed in cleaved caspase 3 expression in tumors of Losartan-treated animals (Figure 1d, 0.5% in controls versus 1% in Losartan-treated)
Summary
Breast cancer is the most frequently diagnosed cancer in women, with an estimated 1.38 million new cases per year [1]. While breast cancer can be detected early and treated successfully, approximately 25% of patients become resistant to adjuvant treatments leading to advanced metastatic disease with poor prognosis. This highlights the necessity for new treatment options. We know that the RAS components, the AT1R, are expressed in normal and tumor cell types including ovary, prostate, pancreas, breast and gut (reviewed by George et al [10]). As the RAS is expressed locally in tissues including the breast, it is most likely to be important for the regulation of “local” normal physiology in these organs. Aberrant RAS component expression may evoke tissue-specific processes of malignant transformation [10]
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