Acyl-CoA synthetase 4 a novel target for hormonal resistance breast cancer

CASTILLO, ANA FERNANDA; ORLANDO, ULISES; PODESTÁ, ERNESTO J; MALOBERTI, PAULA; SOLANO, ANGELA

Houston, Texas

Conferencia; GAP 2015 Conference; 2015

The University of Texas MD Anderson Cancer Center

Abnormal expression of acyl-CoA synthetase-4 (ACSL4) has been documented in colon adenocarcinoma, hepatocellular carcinoma and breast cancer. ACSL4 belongs to a five-member family of enzymes that esterify mainly AA into acyl-CoA. We have developed a stable transfection model using the tetracycline Tet-Off system (MCF-7 Tet-Off/ACSL4) in MCF-7 cells, a model of non-aggressive breast cancer cells, and have proven that their sole transfection with ACSL4 cDNA renders a highly aggressive phenotype in vitro and in vivo?. Immunohistochemical analysis of tumor from MCF7-Tet-Off/ACSL4 breast cancer cells showed few positive cells expressing ER and very few stained for PR. Targeting ACSL4 in cells and in tumors do reverse loss of ER expression. These results suggest that the expression of ACSL4 negatively controlled the expression of ER and may be one of the first events in the transformation of the ER and PR positive phenotype into negative one as shown for the MDA-MD-231 human breast tumor xenograft. These results concord with results showing that in samples from human breast tumor the expression of ACSL4 correlates with the absence of ER We also demonstrate that specific pathways such as AKT-mTOR-SP6 kinase and WNT are functionally required for ACSL4 action. Our interpretation of these data is that with the inhibition of ACSL4 the tumor would be forced to restore the estrogen-signaling pathway for continuous growth and hormonal sensitivity. Blocking both, the ACSL4 and estrogen pathways together, therefore, the tumor might be left with extremely fewer growing options. Finally, by means of a combination of ACSL4 and mTOR inhibitors and ER inhibitors, we demonstrate a synergistic effect in the inhibition of cell growth. In conclusion, ACSL4 is an upstream regulator of tumorigenic pathways and our data provide novel insights into a combined pharmacological approach. Because aggressive phenotype in tumors is the early steps in metastatic progression, the previously unknown mediators of ACSL4 might become valuable prognostic tools or therapeutic targets in breast cancer.