Abstract
Galectin-1 is a β-galactoside binding protein secreted by many types of aggressive cancer cells. Although many studies have focused on the role of galectin-1 in cancer progression, relatively little attention has been paid to galectin-1 as an extracellular therapeutic target. To elucidate the molecular mechanisms underlying galectin-1-mediated cancer progression, we established galectin-1 knock-down cells via retroviral delivery of short hairpin RNA (shRNA) against galectin-1 in two triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and Hs578T. Ablation of galectin-1 expression decreased cell proliferation, migration, invasion, and doxorubicin resistance. We found that these effects were caused by decreased galectin-1-integrin β1 interactions and suppression of the downstream focal adhesion kinase (FAK)/c-Src pathway. We also found that silencing of galectin-1 inhibited extracellular signal-regulated kinase (ERK)/signal transducer and activator of transcription 3 (STAT3) signaling, thereby down-regulating survivin expression. This finding implicates STAT3 as a transcription factor for survivin. Finally, rescue of endogenous galectin-1 knock-down and recombinant galectin-1 treatment both recovered signaling through the FAK/c-Src/ERK/STAT3/survivin pathway. Taken together, these results suggest that extracellular galectin-1 contributes to cancer progression and doxorubicin resistance in TNBC cells. These effects appear to be mediated by galectin-1-induced up-regulation of the integrin β1/FAK/c-Src/ERK/STAT3/survivin pathway. Our results imply that extracellular galectin-1 has potential as a therapeutic target for triple-negative breast cancer.
Highlights
Triple-negative breast cancers (TNBCs) are defined as a subset of breast tumors with absent or low levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression [1]
The results indicate that galectin-1 attached to other cell surface receptor protein after secretion
Much effort has been spent in the identification of a specific therapeutic marker that can be used as a TNBC target molecule
Summary
Triple-negative breast cancers (TNBCs) are defined as a subset of breast tumors with absent or low levels of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression [1]. Since they lack expression of these three receptors, patients with TNBC have limited treatment options and short life expectancies and are associated with poor prognosis [2, 3]. Few reports have investigated the potential of galectin-1 as an extracellular therapeutic target, primarily because galectin-1 is predominantly a secretory protein. We were motivated to investigate the potential of galectin-1 as a TNBC-specific extracellular therapeutic target molecule, even though galectin-1 is a typical secretory protein
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