The RANK Pathway in Breast Cancer: Src Plays a Role!
Rong Li, Thuy Nguyen, Christopher Kragel, Kui Zhang, William E Grizzle, Omar Hameed, Gene P Siegal, Shi Wei. University of Alabama at Birmingham, Birmingham, AL
Background: Receptor activator of nuclear factor κB (RANK) and its ligand, RANKL, are essential for mammary gland development. The molecules also play a key role in osteoclastogenesis and osteolytic bone metastasis. Previous studies suggested that RANKL expression was inversely correlated with the metastatic phenotype in breast cancer (BC), and RANK expression was a poor prognostic factor in BC with bone metastasis. Src, a nonreceptor tyrosine kinase overexpressed in 70-100% of BCs, plays a key role in several transduction pathways. The RANK cytoplasmic tail associates with Src, leading to activation of anti-apoptotic signaling. The aim of this study was to examine the expression of these molecules in BC and to investigate their potential roles in metastasis.
Design: Tissue microarrays (triplicate 1-mm cores/case), constructed from 62 primary BC cases with known metastasis and 10 control BC cases (no relapse for > 8 years of follow up), were stained with RANKL, RANK and Src antibodies. The intensity and percentage of tumor cell staining were multiplied to determine an H-score.
Results: Neither RANKL or RANK expression was significantly different in BCs with and without metastasis, or associated with a bone metastatic phenotype in BCs with metastasis. Interestingly, a significantly lower level of RANKL and a significantly higher level of RANK were found in triple-negative (TN) BCs when compared to luminal BCs (p<0.01, p<0.05)), whereas expression levels of the two molecules in the HER2 subtype were between luminal BCs and TNBCs. Given that TNBCs reportedly have a higher predisposition for brain metastases, it is not surprised that expression of these molecules was significantly associated with a brain metastatic phenotype (both p=0.01). RANK expression was additionally associated with multiple organ metastases (p<0.01). Similar to RANK, Src expression was also significantly higher in TNBCs (p<0.05), BCs with brain metastases (p<0.05) and BCs with multiple organ metastases (p<0.01), but was not associated with a bone metastatic phenotype, a finding consistent with gene expression profiling. Further, a strong linear correlation was found between RANK and Src expression (r=0.6, p<0.0001).
Conclusions: Despite their high expression in bone, RANKL or RANK expression is not associated with BC bone metastasis. Rather, they differ significantly between molecular subtypes. The strong correlation of RANK and Src expression suggests that Src may be a downstream effector of RANK in BC cells. Thus, targeted therapy to these molecules may lead to success, especially in TNBCs, for which there are only limited effective treatment options.
Monday, March 4, 2013 1:00 PM
Poster Session II # 272, Monday Afternoon