Targeting of breast cancer with non-oncology drugs – possible novel therapeutic option for triple-negative breast cancer.

Abstract

Abstract Abstract #2119 Introduction: Triple-negative breast cancer (TNBC) is defined by lack of ER, and PR expression and normal HER2 expression. It is characterized by aggressive biological presentation and unfavorable outcome. It is associated with frequent lack of response to current chemotherapy agents. Recently, 392 drugged genes that serve as targets for 1557 both oncologic and non-oncologic drugs were identified from the pharmacologic database DrugBank (Lauss et al. Pharmacogenomics 2007). In this study, we compared expression levels of these known drug targets between TNBC and receptor-positive cancers. Methods: Gene expression profiles were obtained from fine needle biopsies of newly diagnosed early stage breast cancer before any therapy (n=133, MDACC dataset). Differential expression of these genes was validated in a second independent data set (n=286, Rotterdam dataset) and in a panel of cell lines (n=19). In order to assess the functional relevance of known drug targets overexpressed in TNBC we performed in vitro experiments. Cell lines were treated with various concentrations of selected drugs alone or in combination with paclitaxel. Results: We mapped 675 U133A probe sets representing 347 unique drug targets to the Affymetrix U133A Genechip. 44 drug targets were overexpressed in TNBC compared to non-TNBC in the MDACC dataset. Thirty-three of these (75%) were also overexpressed among TNBC compared to non-TNBC in the Rotterdam dataset. Glutathione-S-transferase pi (GSTpi, target of clomipramine) was the most highly and consistently overexpressed target in human TNBC and in estrogen- and HER2-receptor-negative breast cancer cell lines. The GSTpi overexpressing (and triple negative) human mammary cell line HBL-100 showed dose-dependent inhibition of growth after 144 hrs of incubation with clomipramine, whereas growth of the GSTpi-low expressing (non-triple negative) breast cancer cell lines MCF-7 and SKBR3 was not inhibited by this drug. Treatment with clomipramine did not alter sensitivity to paclitaxel in either cell line in vitro. Conclusion: Gene expression analysis indicates that targets for several known drugs are over expressed in TNBC relative to other types of breast cancers. We hypothesize that some of these drugs may influence the behavior of TNBC and may represent future therapeutic options. Further experiments are needed to fully explore the functional implications of these findings; however, our preliminary results suggest that inhibition of GSTpi with clomipramine leads to inhibition of cell growth of TNBC cell lines in vitro. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2119.