CYTOPLASMIC Fra-1 AND c-Fos: POTENTIAL TARGETS FOR BREAST CANCER THERAPY

RACCA, ANA C.; PRUCCA, CÉSAR G.; CAPUTTO, BEATRIZ L.

Heidelberg

Workshop; EMBO Course: High-Throughput Microscopy for Systems Biology; 2015

EMBL

Breast cancer is the most common cancer in women worldwide. Most cases in less developed countries are diagnosed at late stages, so, development of new therapies to eliminate established tumors is essential.Tumor cells require high rates of phospholipid (pl) synthesis to support membrane biogenesis necessary for their exacerbated growth. Fra-1 and c-Fos activate pl synthesis to sustain proliferation and are highly expressed in breast tumors contrasting with their undetectable levels in the normal control. c-Fos activates particular enzymes of the pl synthesis pathway at the endoplasmic reticulum by physically interacting with them. As Fra-1 is highly homologous to key domains of c-Fos, we propose a shared mechanism for this function. Here, we demonstrate by in vitro enzymatic reactions that Fra-1, like c-Fos, activates CDP-DAG synthase (CDS) in MDA-MB231 cells. None of them affect phosphatidylinositol synthase activity. Similar experiments performed with deletion mutants show that CDS activation is mediated by the basic domain of Fra-1. FRET experiments revealed that Fra-1 binds to CDS through its N-terminal domain. Moreover Fra-1 and c-Fos´s N-terminal domains act as a negative dominant peptides to prevent breast tumor cell proliferation in vitro and toghethet they decrease breast tumor growth rate in Blab/c mice.These results highlight cytoplasmic Fra-1 and c-Fos as potential targets for a novel breast cancer therapy by inhibition of pl synthesis.