Effects of Eribulin on Epithelial–Mesenchymal Plasticity in Patient-Derived Breast Cancer Cultures and Excised Tissues

TL;DR

This study explores how eribulin affects cancer cell behavior in breast cancer tissues and cell lines, showing it can reverse a process linked to treatment resistance.

Contribution

The study demonstrates eribulin's ability to induce epithelial-like characteristics in breast cancer cells and improve chemotherapy response in specific cancer types.

Findings

Eribulin reduced EMT marker expression more effectively than standard chemotherapy in breast cancer patients.

Eribulin exposure increased E-cadherin expression in triple-negative breast cancer cells.

HER2-enriched breast cancer cells showed increased sensitivity to doxorubicin after eribulin treatment.

Abstract

Eribulin is an approved therapy for the treatment of breast cancer which has been shown to reverse the epithelial-to-mesenchymal transition (EMT) and improve the efficacy of standard chemotherapies in cell lines, animal studies, and clinical specimens. Tumour EMT status has also been linked to eribulin efficacy. Based on this, we evaluated the effects of eribulin in patient-derived breast cancer cultures and a triple-negative breast cancer cell line to assess changes to EMT and therapy response. We further identified the induction of epithelial-like characteristics, including E-cadherin expression in a patient-derived HER2+ primary tissue with a predominantly mesenchymal phenotype following longitudinal eribulin exposure. Additionally, we compared EMT marker expression in breast cancers treated with standard-of-care neoadjuvant docetaxel, Adriamycin and cyclophosphamide (TAC) therapy with that observed in the neoadjuvant eribulin clinical trial.

Background: The cytotoxic agent eribulin has been shown to promote EMT reversion, reduce treatment resistance, and potentially enhance responses to a range of therapeutic agents. Methods: We examined the effects of eribulin in patient-derived breast cancer tissues and a phenotypically heterogeneous breast cancer cell line to assess EMT and chemotherapy response. Results: Nanostring-based analysis of EMT-associated gene expression in breast cancers from patients receiving standard-of-care TAC neoadjuvant chemotherapy compared to a cohort receiving neoadjuvant eribulin (NeoEribulin trial) showed markedly reduced expression of EMT markers in cancers treated with eribulin versus TAC. Through single-cell immunofluorescent imaging and analysis, we identified that HCC38 triple-negative breast cancer (TNBC) cells exhibited a shift towards an epithelial-like state marked by E-cadherin upregulation following acute eribulin exposure, but not with other chemotherapeutic agents. Investigation of primary breast cancer cultures derived from pre-neoadjuvant biopsies also revealed that HER2-enriched primary breast cancer cells displayed heightened chemosensitisation to doxorubicin (Adriamycin), which was not recapitulated in TNBC cultures. Conclusions: Our data highlight the presence of contextual parameters which govern the degree of EMT regulation by eribulin.

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