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A galectin‐3 sequence polymorphism confers TRAIL sensitivity to human breast cancer cells
Author(s) -
Mazurek Nachman,
Byrd James C.,
Sun Yunjie,
Ueno Suguru,
Bresalier Robert S.
Publication year - 2011
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.26078
Subject(s) - breast cancer , genotype , cell culture , galectin , doxorubicin , microbiology and biotechnology , cancer research , medicine , biology , cancer , immunology , genetics , gene , chemotherapy
Abstract BACKGROUND: A common polymorphism, rs4644, coding for Pro64 or His64 of the carbohydrate‐binding protein galectin‐3, influences the susceptibility of galectin‐3 to cleavage by matrix metalloproteinases and is associated with breast cancer incidence. Because forced expression of galectin‐3 in a galectin‐3 null breast cancer cell line confers sensitivity to tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), the authors sought to determine whether the His64/Pro64 polymorphism of galectin‐3 affects the sensitivity to TRAIL. METHODS: Genomic DNA of breast cell lines was analyzed for the single nucleotide polymorphism rs4644, and cytotoxicity was determined with the MTT assay. RESULTS: When a collection of 9 breast cancer cell lines that express galectin‐3 was examined for lectin, galactoside‐binding, soluble, 3 ( LGALS3 ) genotype and sensitivity to doxorubicin and TRAIL, doxorubicin sensitivity was not found to be related to LGALS3 genotype. In contrast, none of the 5 cell lines that were homozygous for Pro64 galectin‐3 were found to be sensitive to TRAIL, but 2 of 2 homozygous His64 cell lines and 1 of 2 heterozygous His64 cell lines were sensitive to TRAIL. Forced expression of galectin‐3 of defined genotype in galectin‐3 null cells was used to more directly test the effect of the Pro64His mutation on TRAIL sensitivity. High levels of expression of His64 galectin‐3 rendered BT549 cells sensitive to TRAIL and resistant to doxorubicin, but cells expressing Pro64 galectin‐3 remained resistant to TRAIL and sensitive to doxorubicin. CONCLUSIONS: The results of the current study indicate that the naturally occurring Pro64His mutation in galectin‐3 increases sensitivity to death receptor‐mediated apoptosis. This finding could be relevant to disparities in breast cancer outcomes across population groups, and could guide the design of future clinical trials of TRAIL‐based therapies. Cancer 2011;. © 2011 American Cancer Society.