Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma
G Peiró1, F Ortiz-Martínez2, A Gallardo3
11] Department of Pathology, University General Hospital of Alicante, Pintor Baeza 12, Alicante 03010, Spain [2] Research Unit, University General Hospital of Alicante, Pintor Baeza 12, Alicante 03010, Spain.
Background:
Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas.
Methods:
We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients' outcome.
Results:
Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab.
Conclusions:
Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients.
Insights
Active Src signaling contributes to trastuzumab resistance in HER2-positive breast cancer. Blocking Src may improve outcomes, particularly in hormone receptor-negative tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Src is a non-receptor tyrosine kinase crucial for cell signaling and growth pathways.
- Investigating active Src in response to trastuzumab is key for understanding HER2-positive breast cancer treatment.
Purpose of the Study:
- To explore the role of active Src in trastuzumab resistance in HER2-positive breast carcinomas.
- To correlate Src activation with clinical factors and patient outcomes.
Main Methods:
- Analysis of 278 HER2-positive breast cancer patients (trastuzumab-treated and untreated).
- Immunohistochemistry for active Src and PI3K/Akt/mTOR pathway proteins.
- PIK3CA mutational analysis and in vitro studies using cancer cell lines.
Main Results:
- Increased active Src (pSrc-Y416) found in trastuzumab-resistant cells and 37.8% of tumors.
- Positive correlation of active Src with tumor progression markers (size, necrosis, metastasis) and MAPK activation.
- Inverse correlation with EGFR and p27; association with shorter survival in specific early-stage HER2/hormone receptor-negative tumors.
Conclusions:
- Src activation is implicated in trastuzumab resistance and poor prognosis in HER2-positive breast cancer.
- This effect is more pronounced in HER2/hormone receptor-negative subtypes.
- Targeting the Src pathway could offer therapeutic benefits for these patients.
More Related Videos
13:59High-Content Screening Assay for the Identification of Antibody-Dependent Cellular Cytotoxicity Modifying Compounds
Published on: August 18, 2023
13:19Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
Published on: April 26, 2024
Related Concept Videos
02:56Treatment Resistant Cancers
02:56Treatment Resistent Cancers
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...