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Galectin-3 enhances trastuzumab resistance by regulating cancer malignancy and stemness in HER2-positive breast cancer cells.

ABSTRACT:

Purpose

The aim of this study was to explore the role of galectin-3 in human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells and the potential mechanism.

Methods

Kaplan-Meier (KM)-plot and The Cancer Genome Atlas (TCGA) databases were used to study the role of galectin-3 in the prognosis of HER2-positive breast cancer. The effects of galectin-3 on cell proliferation, migration, invasion, and colony formation ability in HER2-positive breast cancer cells were examined. The relationship between galectin-3 and important components in the HER2 pathways, including HER2, epidermal growth factor receptor (EGFR), protein kinase B (AKT), and phosphatase and tensin homolog (PTEN), was further studied. Lentivirus and CRISPR/Cas9 were used to construct stable cell lines. Cell counting kit-8 (CCK-8) and apoptosis assays were used to study the relationship between galectin-3 and trastuzumab. The effect of galectin-3 on cell stemness was studied by mammosphere formation assay. The effects of galectin-3 on stemness biomarkers and the Notch1 pathway were examined. Tumorigenic models were used to evaluate the effects of galectin-3 on tumorigenesis and the therapeutic effect of trastuzumab in vivo.

Results

HER2-positive breast cancer patients with a high expression level of LGALS3 (the gene encoding galectin-3) messenger RNA (mRNA) showed a poor prognosis. Galectin-3 promoted cancer malignancy through phosphoinositide 3-kinase (PI3K)/AKT signaling pathway activation and upregulated stemness by activating the Notch1 signaling pathway in HER2-positive breast cancer cells. These two factors contributed to the enhancement of trastuzumab resistance in cells. Knockout of LGALS3 had a synergistic therapeutic effect with trastuzumab both in vitro and in vivo.

Conclusions

Galectin-3 may represent a prognostic predictor and therapeutic target for HER2-positive breast cancer.

SUBMITTER: Chen Y

PROVIDER: S-EPMC9250839 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTrastuzumab is a drug that targets the receptor tyrosine kinase HER2 and is essential for the treatment of HER2-positive breast cancer. Resistance to the drug leads to severe consequences, including disease recurrence, tumor enlargement, and metastasis. We hypothesized that trastuzumab treatment might be associated with phenotypic switching in HER2-positive breast cancer cells (BCCs), enabling them to escape and survive the effect of trastuzumab.MethodsWe conducted comprehensive immunophenotyping to detect phenotypic changes in HER2-positive BCCs treated with trastuzumab, based on criteria determined a priori. Based on immunophenotyping results, we characterized the vascular phenotypes of HER2-positive BCCs by western blotting, real-time RT-PCR, and tube formation assay. The vascular phenotype of tumor cells from clinical samples was evaluated by staining with periodic acid-Schiff and an anti-CD31 antibody. We explored small molecule inhibitors that suppress tube formation and determined the inhibitory mechanism.ResultsOut of 242 cell surface antigens, 9 antigens were significantly upregulated and 3 were significantly downregulated by trastuzumab treatment. All upregulated antigens were related to endothelial and stem cell phenotypes, suggesting that trastuzumab treatment might be correlated to switching to a vascular phenotype, namely, vasculogenic mimicry (VM). Several VM markers were upregulated in trastuzumab-treated cells, but these cells did not form tubes on Matrigel, a functional hallmark of VM. Upon analysis of three trastuzumab-resistant HER2-positive cell lines, we found that all three cell lines showed tube formation on Matrigel in the presence of angiogenic growth factors including EGF, FGF2, IGF1, or VEGF. Clinically, VM channels significantly increased in surviving cancer cell clusters of surgically removed tumors pretreated with trastuzumab and chemotherapy compared to both surgically removed tumors without prior systemic treatment and tumors biopsied before presurgical treatment with trastuzumab. Finally, we found that salinomycin completely suppressed VM in all three trastuzumab-resistant cell lines through disruption of actin cytoskeletal integrity.ConclusionsVM promotes metastasis and worsens patient outcomes. The present study indicates that HER2-positive BCCs can exhibit VM in an angiogenic microenvironment after eventually acquiring trastuzumab resistance. The clinical finding supports this in vitro observation. Thus, targeting VM might provide a therapeutic benefit to patients with HER2-positive breast cancer.

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