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Role of CD47 in triple negative breast cancer
Author(s) -
Kaur Sukhbir,
Singh Satya,
Elkahloun Abdel,
Wu Weiwei,
Song Tim,
Arora Ashi,
Roberts David
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.890.5
Subject(s) - cd47 , cd44 , cancer stem cell , cancer research , cd24 , triple negative breast cancer , cancer cell , thrombospondin 1 , cancer , biology , microbiology and biotechnology , cell , breast cancer , stem cell , chemistry , immunology , antibody , angiogenesis , genetics
CD47 is a ubiquitously expressed cell surface receptor for thrombospondin‐1 and SIRPα. High expression of CD47 on several types of cancer cells has been identified as a ‘don't eat me signal' that inhibits their killing by macrophages or NK cells. Conversely, the CD47 antibody B6H12 blocks SIRPα binding and enhances macrophage‐dependent clearance of tumors in several mouse models, although others have shown that such clearance is independent of SIRPα signaling. Cancer stem cells (CSCs) have been reported to express elevated CD47 levels, but the role of CD47 in regulating CSC function has not been examined. Subpopulations enriched in breast CSCs were isolated from the triple negative MDA‐MB‐231 cell line by selection for weak substrate adhesion or by sorting for CD44 ++ and CD24 ‐‐ expression. Treatment with B6H12 inhibited proliferation of the CSCs and suppressed their asymmetric cell division. Global analysis of gene expression of CSCs treated with B6H12 showed up‐regulation of tumor suppressor, apoptotic genes and RNAi silencing but decreased expression of EGFR. We further found that treatment with B6H12 disrupted the interaction between CD47 and EGFR, and inhibited EGF induced EGFR‐tyrosine phosphorylation. B6H12 specifically targeted breast CSCs but not differentiated cancer cells, and this CD47 signaling was independent of SIRPα but associated with K63 ubiquitination of EGFR and its release in exosomes. Our study shows that a candidate therapeutic CD47 antibody targets breast CSCs by down‐regulating cell surface expression of EGFR. This novel mechanism makes CD47 blocking antibodies an attractive therapeutic candidate for treating triple negative breast cancer.