The renin-angiotensin system (RAS) is a key endocrine pathway involved in the regulation of cardiovascular and neuroendocrine function. It is now known that the renin-angiotensin system has local effects in the mammary in mediating regulating the proliferation and differentiation of mammary glandular structures. There is emerging evidence of the dysregulation of RAS in breast cancer; however little is known about RAS-dependent pathways involved in tumour initiation and development. The RAS comprises of angiotensinogen, cleaved by an enzyme, renin o produce angiotensin I, which is the modified by the angiotensin-converting enzyme (ACE) into angiotensin II (AngII). AngII is the classical main effector endocrine hormone that acts via the GPCR, AT1R. In breast tumours, the AGTR1 gene encoding AT1R is amplified in 10–20% of breast cancers, specifically in ER+ve/HER2-negative tumors correlating with poor prognosis.
To elucidate the in vivo relevance of AT1R signaling in mammary tumor initiation and development, we investigated the effects of the AT1R inhibitor, Losartan, in a spontaneously induced mammary tumor model using combined treatment of medroxyprogesterone acetate (MPA) and a carcinogen (7,12-dimethylbenzanthracene (DMBA)). Losartan treatment significantly delayed tumour latency of MPA+DMBA-induced mammary tumors. Analysis of tumor histopathology revealed 100% of the tumours in the control, vehicle treated group were invasive and mixed histology of DCIS and IDC. Most tumours resembled high grade or metaplastic carcinoma with prominent squamous differentiation. In contrast, in the Losartan-treated group, in 70% of the animals, tumours that developed were in the majority classified as DCIS and very few exhibiting an invasive pathology. Our experimental findings suggest that the specific inhibition of AT1R, with Losartan treatment, in the MPA+DMBA mammary tumour model delays tumor latency and progression towards an invasive phenotype. This is the first demonstration that prophylactic use of Losartan delays onset and progression of mammary tumours.