The inhibitory effects of butein on cell proliferation and TNF-α-induced CCL2 release in racially different triple negative breast cancer cells

Abstract

Breast cancer drug resistance is the leading cause of cancer-related mortality in women, and triple negative breast cancer (TNBC) is the most aggressive subtype, affecting African American women more aggressively compared to Caucasians. Of all cancer-related deaths, 15 to 20% are associated with inflammation, where proinflammatory cytokines have been implicated in the tumorigenesis process. The current study investigated the effects of the polyphenolic compound butein (2',3,4,4'-tetrahydroxychalcone) in cell proliferation and survival, as well as its modulatory effect on the release of proinflammatory cytokines in MDA-MB-231 (Caucasian) and MDA-MB-468 (African American) TNBC cell. Results showed that butein decreased cell viability in a time and dose-dependent manner and after 72-h of treatment, cell proliferation rate was reduced in both cell lines. In addition, butein presented higher potency in MDA-MB-468, exhibiting anti-proliferative effects in lower concentrations. Apoptosis assays demonstrated that butein increased apoptotic cells in MDA MB-468, showing 90% of the analyzed cells in the apoptotic phase, compared to 54% in MDA-MB-231 cells. Additionally, butein downregulated both, protein and mRNA expression of CCL2 proinflammatory cytokine and IKBKE in Caucasian cells, but not in African Americans. This study demonstrates butein potential in cancer suppression showing a higher cytotoxic, anti-proliferative, and apoptotic effects in African Americans, compared to Caucasians TNBC cells. It also reveals the butein inhibitory effect on CCL2 expression with a possible association with IKBKE downregulation in MDA-MB-231 cells only, indicating that Caucasians and African Americans TNBC cells respond differently to butein treatment. The obtained findings may provide an explanation regarding the poor response to therapy in African American patients with advance TNBC.