Potential utility of angiotensin II receptor blockers in the treatment of estrogen receptor positive infiltrating ductal carcinoma.

Abstract

Abstract Abstract #2125 Despite significant advances in diagnosis and treatment, breast cancer remains the world's leading cause of cancer mortality in women. In this study we employed differential expression analysis tools to mine the BioExpress®(1) database of transcriptional profiles and found that Angiogtensin II receptor 1 (AT1-R) mRNA expression was highly correlated with expression of estrogen receptor alpha (ERα) in biopsies from patients with infiltrating ductal carcinoma (IDC). Specifically, AT1-R transcript was up-regulated 12.5 fold in ER+ primary IDC relative to ER- primary IDC (P = 0.0001).
 Experiments using ER+ (T47D) and ER– (HCC1143) breast cancer cell lines derived from human mammary gland ductal carcinoma demonstrated that only the ER+ line responded to angiotensin II-mediated growth stimulation, and this effect was dramatically suppressed in a concentration dependent manner by AT1-R blockers (ARBs). Additional cell culture experiments evaluating eight cell lines derived from IDC further validated the concept that co-expression of both ERα and AT1-R was required for responsiveness to angiotensin II-induced cell proliferation. We have also found that ARBs significantly enhanced the anti-proliferative activity of both tamoxifen, an ER modulator, and formestane, an aromatase inhibitor. Most importantly, we have shown in a T47D tumor xenograft model that ARBs, candesartan and irbesartan, dose-dependently inhibited tumor progression in NODScid mice. Currently, we are evaluating the synergistic/additive effects of ARBs with tamoxifen in additional T47D xenograft models.
 In conclusion, our data provides evidence that ARBs may have utility in the prevention and treatment of ER+ IDC. These observations further validate reports that ARBs may suppress tumor cell proliferation, angiogenesis, and cancer progression. To our knowledge our findings represent the first example of a potential means to stratify a patient population for ARB-based tumor therapy using a clinically accepted biomarker, findings which may have significant clinical implications for the treatment of IDC.
 1) BioExpress® is a knowledgebase of human disease biology comprising over 20,000 individual patient samples profiled over the entire human transcriptome representing > 400 disease states including approximately 200 human breast cancer samples (169 diagnosed as IDC) and 68 normal breast tissue controls. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2125.