Abstract 3896: A metabolic enzyme as a pro-angiogenic activator in premalignant mammary cells.

Abstract

Abstract A crucial step in cancer progression is the development of a high-density vascular network, the angiogenic switch. During carcinogenesis breast angiogenesis occurs at hyperplasia before atypia, reaching maximum vascularization between ductal carcinoma in situ and invasive carcinoma. Altered energy metabolism is an early hallmark of several human malignancies. Fatty Acid Synthase (FASN) is a metabolic enzyme that catalyzes the synthesis of Palmitate from Malonyl CoA. With the exception of liver and adipose tissue, normal cells have low levels of FASN and activity. Here we show that FASN expression is progressively up-regulated in the early steps of human breast carcinogenesis. While under hypoxia FASN expression is downregulated in non-transformed breast epithelial cells that form normal ducts. In pre-malignant breast cancer lesions under similar conditions, FASN expression is upregulated. These data suggest a link between FASN-hypoxia-progression. In addition, we observed that in early stages of breast carcinogenesis, FASN regulates the expression of hypoxia genes, which in turn results in increase vascularization and angiogenic markers. Forced expression of FASN in non-transformed breast epithelial cells resulted in increased activity of HIF-1α and upregulation of VEGF expression. Furthermore, FASN-expressing non-transformed breast epithelial cells under hypoxia conditions produced the necessary factors to stimulate angiogenesis, as measured by tube formation and migration in HUVEC cells. These data provide evidence that FASN promotes pro-angiogenesis under hypoxia at the early onset of breast carcinoma; thus, it could be considered as a target for breast cancer chemoprevention. Citation Format: Anatilde M. Gonzalez-Guerrico, Ingrid Espinoza, Ruth Lupu. A metabolic enzyme as a pro-angiogenic activator in premalignant mammary cells. [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 3896. doi:10.1158/1538-7445.AM2013-3896