Supplementary Material & Methods, tables, movie legend from Breast Cancer Targeting through Inhibition of the Endoplasmic Reticulum-Based Apoptosis Regulator Nrh/BCL2L10

Nougarede, Adrien; Popgeorgiev, Nikolay; Kassem, Loay; Omarjee, Soleilmane; Borel, Stephane; Mikaelian, Ivan; Lopez, Jonathan; Gadet, Rudy; Marcillat, Olivier; Treilleux, Isabelle; Villoutreix, Bruno O.; Rimokh, Ruth; Gillet, Germain

doi:10.1158/0008-5472.22417803.v1

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Supplementary Material & Methods, tables, movie legend from Breast Cancer Targeting through Inhibition of the Endoplasmic Reticulum-Based Apoptosis Regulator Nrh/BCL2L10

journal contribution

posted on 2023-03-31, 01:26 authored by Adrien Nougarede, Nikolay Popgeorgiev, Loay Kassem, Soleilmane Omarjee, Stephane Borel, Ivan Mikaelian, Jonathan Lopez, Rudy Gadet, Olivier Marcillat, Isabelle Treilleux, Bruno O. Villoutreix, Ruth Rimokh, Germain Gillet

-I- Reagents and antibodies. Vectors. RNA preparation & RT-qPCR -II- Supplementary Table 1: Invasive breast carcinomas patient cohort characteristics -III- Supplementary Table 2: Correlation between Nrh protein expression and the clinicopathologic factors of breast cancer -IV- Supplementary Table 3: Multivariate analysis of clinical parameters predicting shorter DMFS -V- Legend of supplementary movie : Time-lapse imaging of dTAT-NDP action on CAL-51 breast cancer cell line

History

ARTICLE ABSTRACT

Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL-2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival, and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum. Mechanistic investigations showed that Nrh made BH4 domain–dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type 1/3 Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and to mediate antiapoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo. Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh.Significance: These findings offer a comprehensive molecular model for the activity of Nrh/BCL2L10, a little studied antiapoptotic molecule, prognostic marker, and candidate drug target in breast cancer. Cancer Res; 78(6); 1404–17. ©2018 AACR.