miR-125a Induces HER2 Expression and Sensitivity to Trastuzumab in Triple-Negative Breast Cancer Lines
Lihi Ninio-Many1, Elad Hikri1, Tamar Burg-Golani1
1Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel.
Abstract:
The EGFR/HER2 signaling network is an effective therapeutic target for HER2-positive cancers, which are known for their aggressive biological course. Evidence indicates that the EGFR/HER2 network plays a role in the aggressive basal-like subtype as well. Here, we studied the potential role of miR-125a-3p as a modulator of the EGFR/HER2 pathway in basal-like breast cancer. Over-expression of miR-125a-3p reduced the migratory capability of MDA-MB-231 cells and led to an increase in the expression of ErbB2 transcript and protein. The induced ErbB2 responded to trastuzumab and underwent internalization and subsequent intra-lysosomal degradation. Trastuzumab treatment further reduced the migratory capability and induced the apoptosis of the cells. An in-vivo mouse model, which supported the in-vitro findings, showed a synergistic effect for miR-125a-3p and trastuzumab. Trastuzumab-treated miR-125a-3p-induced tumors were significantly smaller than control induced tumors. Our findings indicate that, in the basal-like subtype of breast cancer, miR-125a-3p may act as a tumor suppressor. miR-125a-3p induces an increase in the expression of ErbB2 that may render the cells suitable for treatment with anti-HER2 therapies.
Insights
MicroRNA-125a-3p acts as a tumor suppressor in basal-like breast cancer by increasing ErbB2 expression. This enhances sensitivity to trastuzumab, reducing tumor growth and migration.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The Epidermal Growth Factor Receptor (EGFR)/Human Epidermal growth factor Receptor 2 (HER2) signaling network is a key therapeutic target in HER2-positive cancers.
- This pathway is also implicated in the aggressive basal-like breast cancer subtype.
- MicroRNAs (miRNAs) are emerging as critical regulators of cancer pathways.
Purpose of the Study:
- To investigate the role of miR-125a-3p in modulating the EGFR/HER2 pathway in basal-like breast cancer.
- To assess the therapeutic potential of miR-125a-3p in combination with anti-HER2 therapy.
Main Methods:
- Over-expression of miR-125a-3p in MDA-MB-231 basal-like breast cancer cells.
- Assessment of cell migration, ErbB2 transcript and protein levels.
- Treatment with trastuzumab (anti-HER2 therapy).
- In vitro and in vivo (mouse model) studies to evaluate tumor growth and response to therapy.
Main Results:
- Over-expression of miR-125a-3p reduced MDA-MB-231 cell migration.
- miR-125a-3p increased ErbB2 expression, making cells responsive to trastuzumab-induced internalization and degradation.
- Combined miR-125a-3p and trastuzumab treatment significantly reduced tumor size in vivo.
- Trastuzumab treatment further decreased cell migration and induced apoptosis.
Conclusions:
- miR-125a-3p functions as a tumor suppressor in basal-like breast cancer.
- miR-125a-3p upregulates ErbB2, potentially sensitizing cancer cells to anti-HER2 therapies like trastuzumab.
- Combination therapy with miR-125a-3p and trastuzumab shows synergistic anti-tumor effects.
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...