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 cancer1-4. 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 prognosis5. However, there is no evidence so far of a functional contribution of AT1R to breast tumorigenesis. We explored the potential benefit of ARB use in breast cancer patients and clarified the mechanisms associated with its success. Compared to normal breast, high AT1R expression occurs in 73% of tumors, with >10-fold higher AT1R levels observed in 30% of tumors. We show that therapeutic inhibition of AT1R, with Losartan, results in a significant reduction in tumor burden and no mammary tumor incidence in 20% of animals. We observe a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This is associated with reduced tumor IL-6, pSTAT3 and TNF levels, reduced tumor cell proliferation and de-differentiation. Our data demonstrate that the AT1R is a potential therapeutic target, 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.

References: 1. Chae, Y.K., et al. Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins. Cancer investigation29, 585-593 (2011). 2. Keizman, D., et al. Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. Eur J Cancer47, 1955-1961 (2011). 3. Nakai, Y., et al. Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine. British journal of cancer103, 1644-1648 (2010). 4. Wilop, S., et al. Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy. Journal of cancer research and clinical oncology135, 1429-1435 (2009). 5. Rhodes, D.R., et al. AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist. Proceedings of the National Academy of Sciences of the United States of America106, 10284-10289 (2009).

Citation Format: Rhiannon S. Coulson, Siddharth Deb, Matthias Ernst, Andrew Allen, Ashwini L. Chand. The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-257.