CYTOPLASMIC FRA-1 AND c-FOS: POTENTIAL TARGETS FOR SPECIFIC BREAST CANCER THERAPY

RACCA, AC; PRUCCA CG; CAPUTTO BL

Puerto Iguazu

Conferencia; 56th International Conference on the Bioscience of Lipids; 2015

Breast cancer is the most common cancer in women worldwide and is increasing particularly in developing countries where the majority of cases are diagnosed at late stages. Low survival rates in less developed countries can be partially explained by the lack of early detection programs. Consequently, the development of new therapies to eliminate established tumors is essential. Tumor cells require a high rate of phospholipid synthesis to support high rates of membrane biogenesis necessary for their exacerbated growth. We previously demonstrated that Fra-1 and c-Fos activate phospholipid synthesis sustaining proliferation in breast tumor tissues. These proteins are highly expressed in breast tumors contrasting with their undetectable levels in normal breast tissue. c-Fos activates particular enzymes of the pathway of synthesis of phospholipids at the endoplasmic reticulum, by physically interacting with them. Fra-1 is highly homologous to key domains of c-Fos, which allows us to propose a shared mechanism for phospholipid synthesis activation. Herein, we demonstrate examining in vitro enzymatic reactions that Fra-1, like c-Fos, activates the CDP-diacylglycerol synthase (CDS) in a dose dependent manner in MDAMB- 231 cells. Neither c-Fos nor Fra-1 affects phosphatidylinositol synthase activity. Similar experiments performed with deletion mutants indicate that CDS activation is mediated by the basic domain of Fra-1. Moreover, FRET experiments revealed that Fra-1 binds to the enzyme it activates through its N-terminal domain, as occurs with c-Fos.Preliminary results show that the physical association between Fra-1´s N-terminal domain with the enzyme it activates can act as a negative dominant peptide that to prevents breast tumor cell proliferation. These results highlight cytoplasmic Fra-1 and c-Fos as potential targets for a novel breast cancer therapy by inhibition of phospholipid synthesis. As no Fra-1 or c-Fos expression is observed in non-tumor breast cells, this type of therapy should not affect normal breast cells.