Background: Triple-negative breast cancers (TNBC) are defined as not having amplification of the estrogen receptor, progesterone receptor, or epidermal growth factor receptor 2. Recovery of patients is, currently, severely limited after diagnosis of metastatic TNBC, with fewer than 30 % of patients surviving more than 5 years. The most effective therapy to date is chemotherapy, which has been unsuccessful because of lack of therapeutic targets for these aggressive cancers. To identify new molecular targets for TNBC, we have developed a novel method for drug discovery using active compounds for identification of pharmacodynamic biomarkers.
Methods: We used chemical informatics to design a small-molecule library with structural diversity. This library was used to screen for compounds that selectively inhibit proliferation of TNBC cell lines. Different gene-expression profiles in cell lines before and after the addition of selected compounds were analyzed and compared with those of control cells.
Results: We identified (E)-3-(3,4-dihydroxybenzylidene)benzofuran-2(3H)-one (DBBF) which specifically inhibited proliferation of a TNBC cell line, MDA-MB-468, with an IC50 of 2.4 μM. Microarray analysis identified several signaling pathways, including the irinotecan pathway, which changed specifically in the TNBC cell lines on addition of DBBF.
Conclusion: We have developed a novel research strategy that involves screening of selective inhibitors of TNBC cell line proliferation that can be used for identification of pharmacodynamic biomarkers for TNBC. The discovery of new pathways by this technique should lead to the identification of new therapeutic targets for this aggressive cancer.