Abstract
BackgroundTriple-negative breast cancer (TNBC) is a highly diverse group that is associated with an aggressive phenotype. Its treatment has been challenging due to its heterogeneity and absence of well-defined molecular targets. Thus, there is an urgent need to identify novel agents with therapeutic application. NF-κB is over-expressed in many breast cancers; thus, inactivation of the NF-κB pathway could serve as a therapeutic target. Here we report for the first time the anti-tumor activity of panepoxydone (PP), a NF-κB inhibitor isolated from an edible mushroom, in several breast cancer cell lines.MethodsWe investigated the effects of PP on cell growth, migration-invasion, apoptosis and EMT-related proteins expression in MCF-7 and TNBC cell lines MDA-MB-231, MDA-MB-468 and MDA-MB-453.ResultsSignificant antitumor activity was seen in all cell lines, with differential responses noted in cell-line specific manner. Treatment with PP resulted in significant cytotoxicity, decreased invasion, migration and increased apoptosis in all cell lines tested. Up-regulation of Bax and cleaved PARP and down-regulation of Bcl-2, survivin, cyclin D1 and caspase 3 were noted in PP-treated breast cancer cells. The antitumor effect of PP appeared related to its ability to inhibit the phosphorylation of inhibitor of NF-κB (IκBα) with cytoplasmic accumulation. PP treatment also down-regulated FOXM1 which resulted in a reversal of EMT. Similar results were obtained after silencing of NF-kB and FOXM1.ConclusionAltogether, these studies show, for the first time the antitumor activity of PP against breast cancer cells, in particular TNBC cells. Furthermore, it highlights the concept that optimal treatment of TNBC warrants attention to the differential sensitivity of various TNBC subtypes to therapeutic agents. These results suggest that the PP may be a potentially effective chemopreventive or therapeutic agent against breast cancer. However, additional studies are required to more fully elucidate the mechanism of antitumor effect of PP.
Highlights
Breast cancer is one of the most common malignancies in women worldwide and the second leading cause of cancer-related mortality in women
The NF-kBp65 primary antibody was obtained from BD Transduction Laboratories (San Diego, CA) and the Alexaflour 488 immunofluorescence antibody was purchased from Invitrogen (Carlsbad, CA). siFOXM1 and siNF-kB was obtained from Santa Cruz Biotechnology (Santa Cruz, CA) and Cell Signaling Technology (Beverly, MA), respectively
PP exhibited a time and dose-dependent decrease in cell proliferation as early as 24 hrs and this continue to 72 hrs of exposure (Figure 1A), with inhibitory concentration 50 (IC50) values of 4, 5, 6 and 15 mM for MDA-MB-453, MCF-7, MDA-MB-468 and MDA-MB-231 cells, respectively (Figure 1B)
Summary
Breast cancer is one of the most common malignancies in women worldwide and the second leading cause of cancer-related mortality in women. Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer. It is typically characterized as a morphologically high grade tumor demonstrating lack of expression of estrogen (ER), progesterone (PR) and human epidermal growth factor receptors (Her-2). TNBCs behave more aggressively, with patients affected having a worse overall and disease-free survival when compared to other breast cancer subtypes. This has been partially attributed to the insensitivity of TNBCs towards available targeted treatment strategies, such as endocrine and antiHer-2 therapies [7,8]. We report for the first time the anti-tumor activity of panepoxydone (PP), a NF-kB inhibitor isolated from an edible mushroom, in several breast cancer cell lines
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