Obesity is a significant risk factor of breast cancer (BC) and is associated with 20 ~ 40% increased risk in post-menopausal women. One well studied dysregulated mechanism is the renin-angiotensin system (RAS), which is over activated in obesity. Currently RAS inhibitors, angiotensin converting enzyme inhibitor (ACEi) and AT1 receptor blockers (ARBs), are used safely as anti-hypertensive therapies in BC patients. However, it is uncertain whether and how inhibition of RAS in adipose tissue impacts obesity and BC cross-talk. Hence, we hypothesized that adipose RAS inhibition will reduce BC cell motility and inflammation.
We determined (1) direct effects of Ang II (1 nM), ACEi (captopril, 100 uM) or ARB (telmisartan, 10uM) on receptor positive MCF-7 and receptor triple negative MDA-MB-231 cells; and (2) effects of conditioned media (CM) from human adipocytes (differentiated mesenchymal stem cells) with above treatments on BC cells. We conducted protein (western blots and ELISA) and gene (qPCR) expression analyses on BC cells, and assessed BC cell motility using wound healing assays. Data are analyzed by one-way ANOVA using GraphPad Prism (version 5) at a significance p<0.05.
Direct treatments with Ang II, ACEi or ARB did not alter inflammatory cytokines in both BC cell lines. CM from Ang II-treated adipocytes significantly increased secretion of pro-inflammatory markers, while RAS inhibitors reduced their secretion in MDA-MB-231, but not in MCF-7 cells. Additionally, CM from adipocytes treated with RAS inhibitors significantly reduced markers of inflammation, fat synthesis, and angiogenesis in both BC cells. Furthermore, CM from ACEi pretreated adipocytes reduced cell motility in both BC cells.
These results indicate an important role of RAS inhibitors in obesity and breast cancer cross-talk and proposes an alternative therapeutic role of RAS inhibitors in obesity-mediated breast cancer treatment.