Abstract 861: Analysis of predictive genes in triple negative breast cancer in response to a gamma-secretase inhibitor.

Abstract

Abstract Defined by the lack of estrogen and progesterone receptors and amplification of human epidermal growth factor receptor-2 (HER-2), triple negative breast cancer (TNBC) is a devastating disease with no approved, targeted therapy to date. Characterized by aggressive behavior which includes high rates of metastasis and very poor prognosis, TNBC is presently treated with DNA-damaging agents such as cisplatin or carboplatin. The overall survival outcomes for women with TNBC is dismal and consequently TNBC research requires identification of biomarkers that specifically mediate signaling pathways that lead to disease progression and metastasis. Notch receptors which are necessary for self-renewal and survival of breast cancer stem cells are excellent candidate biomarkers to investigate in various subtypes of TNBC. Based on the critical need to identify predictive biomarkers, we hypothesized that inhibition of the Notch pathway via γ-secretase inhibition (GSI) will provide an effective blockade of TNBC growth in specific subtypes where predictive Notch gene expression profiles are significantly up or downregulated. A panel of three TNBC cell lines were used in this study: MDA-MB-231 (mesenchymal stem-like), MDA-MB-468 (basal-like 1), and BT549 (luminal). Using real-time PCR, Notch pathway-associated genes were measured which include Notch-1 and Notch-4 receptors, Notch target genes (i.e. Deltex-1, Hes-1, Hes-5, and Hey-1), and genes such as IL-8 and MMP-9 which are associated with aggressive tumor behavior. Both anchorage-dependent and anchorage-independent growth assays were measured in response to MRK-003 GSI, carboplatin, and the combination. We have identified for the first time a TNBC line (MDA-MB-468) that expressed the highest level of Hes-1, a Notch gene target, and is the most sensitive to single agent MRK-003 GSI treatment. We also identified that this cell line with the highest sensitivity to MRK-003 GSI upregulates Notch-4 and IL-8 in response to the GSI to a greater extent than either of the two other TNBC lines. Furthermore, the addition of carboplatin at its IC50 concentration significantly increased the sensitivity of MRK-003 GSI in otherwise insensitive TNBC lines. These results suggest for the first time that: 1) Hes-1 could potentially be a valuable predictive biomarker of Notch activity in TBNC; 2) induction of Notch-4 and/or IL-8 could predict response to MRK-003 GSI; and 3) carboplatin might provide a means to increase sensitivity to MRK-003 GSI in resistant TNBC. Citation Format: Roma Olsauskas-Kuprys, Clodia Osipo. Analysis of predictive genes in triple negative breast cancer in response to a gamma-secretase inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2013-861