Acyl-CoA synthetase-4, a new potential therapeutic target in hormone-resistant breast cancer

CASTILLO, ANA F.; ORLANDO, ULISES D.; DATTILO, MELINA A.; SOLANO, ANGELA R.; MALOBERTI, PAULA M.; PODESTA, ERNESTO J.

Congreso; 51 Annual Meeting Argentine Society for Biochemistry and Molecular Biology; 2015

Acyl-CoA synthetase 4 (ACSL4) expression, an enzyme working in arachidonic acid metabolism, has been associated with breast carcinoma. The triple-negative tumor (TN) is a subtype of breast cancer that exhibits poor prognosis and no effective therapy is readily available. Therefore, the identification of new therapeutic targets is critical to improve the management of a significant proportion of cancer patients. We show that knocking down ACSL4 expression in TN cell line, MDA-MB-231, induces estrogen receptor (ERα) expression. ACSL4 overexpression decreases the level of ERα. By means of the MCF-7 Tet-Off/ACSL4 model system, which involves a reduction in ERα levels, we used a pharmacological approach to inhibit cell proliferation through a combination of sub-maximal doses of tamoxifen and rosiglitazone, an ACSL4 inhibitor. Drugs alone did not produce a significant inhibition in cell proliferation. However, the combination of the two inhibitors was much more efficient, showing a remarkable synergistic effect. ERα and ribosomal p-S6 protein levels were monitored to confirm that rosiglitazone treatment indeed increased ERα expression and decreased the mTOR signal. The presence of ACSL4 could be a prognostic factor for hormone resistance in ERα-positive breast cancer tissues. A combined therapy could thus be very useful in actually preventing the appearance of hormone resistance.