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Characterization and targeting of chemoresistant triple-negative breast cancer subtypes using amino-pyridine

Santiago Ruiz-Martínez1, Xavi Ribas2, Miquel Costas2

  • 1New Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, Faculty of Medicine, University of Girona, Spain; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Sahlgrenska Center for Cancer Research, University of Gothenburg, Sweden.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|May 11, 2025
PubMed

Insights

Triple-negative breast cancer (TNBC) is heterogeneous and resistant to treatment. Novel compounds show promise in reducing cancer stem cells and enhancing chemotherapy efficacy against TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its heterogeneity, chemoresistance, and cancer stem cells (CSCs).
  • Understanding the molecular underpinnings of TNBC subtypes and their resistant variants is crucial for developing effective treatments.

Purpose of the Study:

  • To characterize the molecular profiles and invasive properties of two distinct TNBC cell lines (MDA-MB-231 and HCC1806) and their chemoresistant derivatives.
  • To investigate the role of CSC markers, epithelial-mesenchymal transition (EMT), and embryonic signaling pathways in TNBC chemoresistance.
  • To evaluate the therapeutic potential of novel polyamine compounds against sensitive and resistant TNBC cells and CSCs.

Main Methods:

  • Comparative analysis of two TNBC cell lines (MDA-MB-231, HCC1806) and their doxorubicin/paclitaxel-resistant variants.
  • Assessment of cancer stem cell markers (CD44, CD24, CD133), EMT markers, and aldehyde dehydrogenase (ALDH) activity.
  • Analysis of embryonic signaling pathways, including Sonic Hedgehog and Notch.
  • In vitro evaluation of novel amino-pyridine polyamine compounds for cytotoxicity, CSC property reduction, and enhancement of standard chemotherapeutics.

Main Results:

  • TNBC cell lines displayed distinct EMT marker profiles and CSC characteristics (CD44+/CD24-/low).
  • Chemoresistant variants showed altered CSC markers (notably CD133 upregulation), EMT gene expression, and ALDH activity.
  • Sonic Hedgehog signaling was prominent in the BL2 subtype, and resistant models showed increased Notch receptor expression.
  • Novel polyamine compounds demonstrated significant cytotoxicity against sensitive and resistant TNBC cells, reduced CSC self-renewal, and potentiated standard chemotherapy.

Conclusions:

  • TNBC exhibits significant molecular heterogeneity, influencing chemoresistance and CSC properties.
  • CD133, Sonic Hedgehog, and Notch signaling pathways are implicated in TNBC chemoresistance.
  • Novel polyamine compounds represent a promising therapeutic strategy to overcome TNBC chemoresistance and target CSCs, enhancing current treatment regimens.
Keywords:
Amino-pyridine compoundsCancer stem cells (CSCs)ChemoresistanceTriple-negative breast cancer (TNBC)

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