Breast cancer targeting through inhibition of the endoplasmic reticulum-based apoptosis regulator Nrh/BCL2L10.
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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 BCL2 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 (ER). 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 I/III Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and mediate anti-apoptosis. 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. |
Year of Publication | :
2018
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Journal | :
Cancer research
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Date Published | :
2018
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ISSN Number | :
0008-5472
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URL | :
http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=29330143
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DOI | :
10.1158/0008-5472.CAN-17-0846
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Short Title | :
Cancer Res
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