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Human breast cancer and lymph node metastases express Gb3 and can be targeted by STxB-vectorized chemotherapeutic
Lev Stimmer, Sabrina Dehay, Fariba Nemati
1Endocytic Trafficking and Therapeutic Delivery Group, UMR3666 CNRS - U1143 INSERM, Institut Curie-Centre de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France. ludger.johannes@curie.fr.
Background:
The B-subunit of Shiga toxin (STxB) specifically binds to the glycosphingolipid Gb3 that is highly expressed on a number of human tumors and has been shown to target tumor cells in mouse models and ex vivo on primary colon carcinoma specimen.
Methods:
Using a novel ex vivo STxB labeling (ESL) method we studied Gb3 expression in cytological specimens of primary human breast tumors from 107 patients, and in synchronous lymph node metastases from 20 patients. Fluorescent STxB was incubated with fine-needle aspiration (FNA) specimens, and Gb3 expression was evaluated by fluorescence microscopy. Furthermore, 11 patient-derived human breast cancer xenografts (HBCx) were evaluated for expression of Gb3 by ESL and FACS. In addition, the biodistribution of fluorescent STxB conjugate was studied after intravenous injection in a Gb3 positive HBCx model.
Results:
Gb3 expression was detected in 62 of 107 patients (57.9%), mainly in epithelial tumor cells. Gb3 positivity correlated with estrogen receptor expression (p≤0.01), whereas absence of Gb3 expression in primary tumors was correlated with the presence of lymph node metastases (p≤0.03). 65% of lymph node metastases were Gb3 positive and in 40% of tested patients, we observed a statistically significant increase of metastatic Gb3 expression (p≤0.04). Using concordant ESL and flow cytometry analysis, 6 out of 11 HBCx samples were scored positive. Intravenous injections of fluorescent STxB into HBC xenografted mice showed preferential STxB accumulation in epithelial cells and cells with endothelial morphology of the tumor.
Conclusion:
The enhanced expression of Gb3 in primary breast carcinomas and its lymph node metastases indicate that the development of STxB-based therapeutic strategies is of interest in this pathology. Gb3 expressing HBCx can be used as a model for preclinical studies with STxB conjugates. Finally, the ESL technique on FNA represents a rapid and cost effective method for the stratification of patients in future clinical trials.
Insights
Shiga toxin B-subunit (STxB) binds to Gb3, a molecule found on breast tumors. This study shows Gb3 is present in many breast cancers and their metastases, suggesting STxB therapies could be effective.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Shiga toxin B-subunit (STxB) binds to glycosphingolipid Gb3.
- Gb3 is highly expressed on various human tumors, including breast cancer.
- STxB has shown potential for targeting tumor cells in preclinical models.
Purpose of the Study:
- To investigate Gb3 expression in primary human breast tumors and lymph node metastases.
- To evaluate the utility of the ex vivo STxB labeling (ESL) method for assessing Gb3 expression.
- To assess the suitability of Gb3-expressing human breast cancer xenografts (HBCx) for preclinical studies.
Main Methods:
- Developed and applied a novel ex vivo STxB labeling (ESL) method.
- Analyzed cytological specimens from 107 primary breast tumors and 20 lymph node metastases using ESL and fluorescence microscopy.
- Evaluated 11 HBCx samples using ESL and fluorescence-activated cell sorting (FACS), and studied STxB biodistribution in vivo.
Main Results:
- Gb3 expression was detected in 57.9% of primary breast tumors and 65% of lymph node metastases.
- Gb3 positivity correlated with estrogen receptor expression and showed increased expression in metastases.
- ESL and FACS confirmed Gb3 expression in 6 out of 11 HBCx samples, with preferential STxB accumulation in tumors in vivo.
Conclusions:
- Enhanced Gb3 expression in breast carcinomas and metastases supports STxB-based therapeutic strategies.
- Gb3-expressing HBCx models are valuable for preclinical STxB conjugate studies.
- ESL on fine-needle aspiration (FNA) specimens offers a rapid, cost-effective patient stratification method for clinical trials.
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