Triple-negative breast cancer (TNBC), an aggressive
breast cancer subtype lacking effective targeted
therapies, is considered to feature a unique cellular microenvironment with high infiltration of tumor-associated macrophages (TAM), which contribute to worsening
breast cancer patient outcomes. Previous studies have shown the antitumoral actions of the dietary omega-3
docosahexaenoic acid (DHA) in both
tumor epithelial and stromal components of the
breast cancer microenvironment. Particularly in
breast cancer cells, DHA can be converted into its conjugate with
ethanolamine,
DHEA, leading to a more effective anti-oncogenic activity of the parent compound in
estrogen receptor-positive
breast cancer cells. Here, we investigated the ability of
DHEA to attenuate the malignant phenotype of MDA-MB-231 and MDA-MB-436 TNBC cell lines, which in turn influenced TAM behaviors. Our findings revealed that
DHEA reduced the viability of TNBC cells in a concentration-dependent manner and compromised cell migration and invasion. Interestingly,
DHEA inhibited oxygen consumption and extracellular acidification rates, reducing respiration and the glycolytic reserve in both cell lines. In a co-culture system, TNBC cells exposed to
DHEA suppressed recruitment of human THP-1 cells, reduced their viability, and the expression of genes associated with TAM phenotype. Interestingly, we unraveled that the effects of
DHEA in TNCB cells were mediated by reduced C-C motif
chemokine ligand 5 (CCL5) expression and secretion affecting macrophage recruitment. Overall, our data, shedding new light on the antitumoral effects of DHA
ethanolamine-conjugated, address this compound as a promising option in the treatment of TNBC patients.