N-TERMINAL DOMAIN OF cFOS AND FRA1: A NOVEL APPROACH TO INHIBIT BREAST TUMOR PROGRESSION

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

Congreso; SAIB 2017 - Reunión conjunta de Sociedades; 2017

Breast cancer is the most common type of cancer and the leadingcause of cancer death in women worldwide. Although early detectionhas improved survival, in less developed countries most casesare diagnosed at late stages when available therapies are notefficient. Highly proliferating breast tumor cells require high ratesof phospholipid (pl) synthesis to support membrane biogenesis fortheir exacerbated growth. Both Fra-1 and c-Fos are overexpressedin breast tumors, contrasting with their undetectable levels in normaltissue and both promote pl synthesis by activating rate limitingenzymes such as CDP-DAG synthase (CDS) through a physicalassociation with the activated enzyme. We have previously demonstratedthat the basic domain of both Fra1 and cFos are involvedin the activation of CDS whereas the N-terminal domain of Fra1/cFos physically associates with CDS. Herein we demonstrate usingin culture experiments, that both N-terminal domains togetherinhibit the proliferation of the breast tumor cell line MDA-MB-231.In vivo, experiments in Balb/c mice bearing tumors generated withthe 4T1 breast tumor cell line, revealed that the treatment with bothN-terminal deletion mutants significantly decreased tumor growthrate. Moreover, inoculating 4T1 cells in both flanks of each mouseeliminated the possibility of a contribution of systemic effect on theresults: One tumor was treated with both N-terminal domains andthe other with vehicle. Tumors treated with the N-terminal domainsgrew to a significantly reduced tumor volume with a decreased tumorgrowth rate when compared with the contralateral vehicle-treatedcontrol present in the same mouse