Abstract

Background

Although ER-positive breast cancer patients have a good prognosis, 30-50% of patients will experience recurrence due to the development of resistance. Cancer cells develop resistance through various signalling pathways including, NFkB pathway. NFkB activation was initially associated with the aetiology and progression of hormone-independent BC. Treatment options for hormonal-resistant breast cancers are limited. Here we exploited the cytotoxicity, antiproliferation and anti-invasion effects of 1’ acetoxychavicol acetate (ACA) on downstream cancer-promoting NFkB regulated genes and proteins (such as CCND1, C-myc, CXCR4, and uPA) on tamoxifen-resistant (MCF7/LCC2) and tamoxifen/fluvestrant-resistant (MCF7/LCC9) breast cancer cells.

Method

Cytotoxicity of ACA was explored in vitro using MTT assays at three different incubation time; 24 h, 48 h, and 72 h. Anti-invasion of ACA was done by Matrigel invasion assay, while the mode of action was elucidated through real-time PCR followed by western blotting analysis.

Results

We showed that ACA significantly inhibited the growth of MCF7, MCF7/LCC2, and MCF7/LCC9 in a dose- and time-dependent manner. We also found that ACA suppressed MCF7/LCC2 and MCF7/LCC9 cells invasion. The effects correlated with downregulation of the proteins involved in cell proliferation (ERK1/2, PI3K/AKT) and invasion (uPA) as well as downregulation of cancer-promoting NFkB regulated genes including, proliferative (CCND1, C-myc), invasive (CXCR4, uPA) biomarkers.

Conclusion

Overall, our findings suggest that ACA exhibits antiproliferative effect through abrogation of ERK1/2, PI3K/AKT, which affect the transcriptional level of CCND1and C-myc while the anti-invasive effect of ACA targets CXCR4 and uPA.