Cytoplasmic Fra1 and cFos as potential targets for breast cancer therapy

RACCA, AC; PRUCCA C.G.; CAPUTTO BL

Córdoba

Congreso; LII Reunión Anual del Sociedad Argentina de Investigación Bioquímica y Biología Molecular.; 2016

Breast cancer is the most common type of cancer and the leading cause of cancer death in women worldwide. In less developed countries, most cases are diagnosed at late stages, so development of new therapies to eliminate established tumors is essential. Phospholipids (pl) are the quantitatively most important components of cell membranes and tumor cells require high rates of pl biosynthesis to support membrane biogenesis for their exacerbated growth. Both Fra-1 and c-Fos are overexpressed in breast tumors contrasting with their undetectable levels in the normal tissue and promote pl synthesis by activating the rate limiting enzyme CDPDAG synthase (CDS) through a physical association with this enzyme. Using in vitro enzymatic reactions we demonstrate that the basic domain of both Fra1 and cFos are involved in the activation of CDS whereas the N-terminal domain of Fra1/cFos physically associates with CDS as evidenced by FRET. We also examined if both N-terminal deletion mutants act as negative dominants to inhibit breast tumor growth by interacting with the enzyme and blocking its activation by their corresponding full length versions. Proliferation of MDA-MB231 cells in culture and in vivo breast tumor growth is significantly inhibited in the presence of either/both deletion mutants in comparison to the respective controls treated with vehicle alone.