Abstract 4378: Targeting the embryonic morphogen Nodal reduces viability of doxorubicin-treated breast cancer cells in vitro

Abstract

Abstract Triple negative breast cancer represents an aggressive malignancy for which few targeted therapies exist. The embryonic morphogen Nodal is re-expressed in highly aggressive breast cancers and reduction of Nodal signaling decreases tumor cell metastatic characteristics. This represents a potential avenue for the development of therapeutics aimed at inhibiting the Nodal pathway. To explore this further, we evaluated Nodal expression in breast cancer cells following chemotherapy. In vitro treatment of MDA-MB-231 and MDA-MB-468 human breast cancer cell lines with Doxorubicin, a chemotherapy commonly used for the treatment of malignant breast cancer, resulted in the generation of surviving subpopulations that retained Nodal expression (>80%) and remained viable. To validate these findings in vivo, we analyzed Doxorubicin treated metastatic patient derived breast cancer xenografts (PDX) which displayed a residual population of Nodal positive cells when analyzed by immunohistochemistry. Based on these findings, we hypothesize that targeting Nodal in a combinatorial approach with chemotherapy will lead to a reduction in remaining viable populations of cancer cells. When we utilized an anti-Nodal neutralizing antibody to inhibit Nodal signaling, antibody treatment reduced cell proliferation, attachment and increased rates of apoptosis in Doxorubicin treated breast cancer cell lines. Decreases in phosphorylation of Histone 3, a marker of cellular proliferation, and increases in the cleavage of PARP, correlating to induction of apoptosis, were noted in response to antibody treatment. These data suggest that Nodal signaling plays a critical role in the growth of metastatic breast cancer cells and targeting Nodal may improve therapeutic outcome in malignancies such as triple negative breast cancer. The initial results highlight translational potential for the development of humanized antibodies capable of inhibiting Nodal function. Citation Format: Thomas M. Bodenstine, Grace S. Chandler, Naira V. Margaryan, Luigi Strizzi, Alina Gilgur, Elisabeth A. Seftor, Richard E B Seftor, Zhila Khalkhali-Ellis, Andrey Ugolkov, Andrew P. Mazar, Mary J C Hendrix. Targeting the embryonic morphogen Nodal reduces viability of doxorubicin-treated breast cancer cells in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4378. doi:10.1158/1538-7445.AM2015-4378