Abstract
Abstract
Breast cancer is the leading cause of morbidity and second-leading cause of death in women worldwide. Breast stromal fibroblasts, the most abundant and the most reactive cells of the tumor stroma, actively promote tumor growth, invasion, migration, angiogenesis and metastasis through elevated secretion of several factors including SDF1, MMP-2 and vascular endothelial growth factor A (VEGF-A). These secretions are under the control of several tumor suppressor genes such as p16, p53 and CAV-1, which were fond to be down-regulated in most active fibroblasts. Therefore, our major aim in this study was to study the potential use of caffeine to up-regulate these tumor suppressor genes and hence reduces the secretion of these cancer-promoting factors. We have shown that low doses of caffeine up-regulate the tumor suppressor proteins p16, p21, p53 and CAV-1 in breast stromal fibroblasts. Consequently, the expression and secretion of MMP-2 and VEGF-A was reduced following caffeine treatment. Moreover, caffeine reduced the expression of SDF-1, TGF-β and α-SMA, three important markers of active fibroblast, suggesting that caffeine has the ability of “normalizing” stromal fibroblasts. To further confirm this, we have shown that caffeine suppresses stromal fibroblast-related enhancement of invasion/migration of breast cancer cells. Importantly, this effect was mediated through caffeine-dependent inactivation of the two major invasion/migration protein kinases Akt and Erk, through up-regulating PTEN in breast stromal fibroblasts. Furthermore, caffeine suppressed the expression/secretion of VEGF-A in breast stromal fibroblasts and their paracrine enhancement of angiogenesis in vitro. This effect was mediated through inhibition of the VEGF-A activator HIF-1α. Therefore, we have clearly shown here that caffeine, a natural and pharmacologically safe product, has the potential to normalize breast stromal fibroblasts and consequently suppresses their paracrine procarcinogenic effects.
Citation Format: Mysoon M. Al Ansari, Abdelilah Aboussekhra. Caffeine normalizes breast stromal fibroblasts and suppresses their pro-carcinogenic effects. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4886. doi:10.1158/1538-7445.AM2013-4886