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Breast Cancer

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01-11-2014 | Original Article

Identification of a novel inhibitor of triple-negative breast cancer cell growth by screening of a small-molecule library

Authors: Tomoyuki Fujita, Tamio Mizukami, Tadashi Okawara, Kengo Inoue, Minoru Fujimori

Published in: Breast Cancer | Issue 6/2014

Abstract

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.

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Title: Identification of a novel inhibitor of triple-negative breast cancer cell growth by screening of a small-molecule library
Authors: Tomoyuki Fujita
Tamio Mizukami
Tadashi Okawara
Kengo Inoue
Minoru Fujimori
Publication date: 01-11-2014
Publisher: Springer Japan
Published in: Breast Cancer / Issue 6/2014
Print ISSN: 1340-6868
Electronic ISSN: 1880-4233
DOI: https://doi.org/10.1007/s12282-013-0452-8

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Abstract

Background

Methods

Results

Conclusion

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