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Updated: Feb 6, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Subtyping Of Triple Negative Breast Carcinoma On The Basis Of RTK Expression
Harald Hessel1, Manuela Poignée-Heger2, Sabine Lohmann2
1Institute of Pathology, Faculty of Medicine, LMU Munich, Germany.
Abstract:
Background: "Triple-negative breast cancers" (TNBC) comprise a heterogeneous group of about 15% of invasive BCs lacking the expression of estrogen and progesterone receptors (ER, PR) and the expression of HER2 (ERBB2) and are therefore no established candidates for targeted treatment options in BC, i.e., endocrine and anti-HER2 therapy. The aim of the present study was to use gene expression profiling and immunohistochemical (IHC) characterization to identify receptor tyrosine kinase (RTK) profiles that would allow patient stratification for the purposes of target-oriented personalized tumor therapy in TNBC. Methods: Twenty-nine cases of TNBC selected according to routine diagnostic IHC/cytogenetic criteria were examined by reverse transcription polymerase chain reaction (RT-PCR). RTK mRNA expression profiles were generated for a total of 31 tumor-relevant biomarkers, mainly belonging to the IGF- and EGF-receptor families but also including biomarkers related to downstream signaling. Protein expression of selected biomarkers was investigated by IHC. Results: Hierarchical cluster analysis revealed a dichotomous differentiation pattern amongst TNBCs. A significant difference in gene expression was observed for 16 of the 31 RTK-associated tumor relevant biomarkers between the two newly identified TNBC subgroups. The findings were verified at the posttranslational level by the IHC data. The RTKs HER4, IGF-1R and IGF-2R and the hormone receptors ER and PR below the IHC detection limit play a central role in the differentiation of the two TNBC subgroups. Observed survival was reported as Kaplan-Meier estimates and point towards an improved survival of patients with RTK-high with superior three-year survival rate of 100% compared to RTK-low gene signatures with superior three-year survival rate of 60% (log-rank test, p-value = 0.022). Conclusion: Gene-expression and IHC analysis of the EGF and IGF receptor families and biomarkers associated with downstream signaling point to the existence of two distinct TNBC subtypes. The RTKs HER4, IGF-1R, IGF-2R and the hormone receptors ER and PR appear to be of particular importance here. Based on survival analysis the differentiation of TNBC with RTK-high and RTK-low gene signatures seems to be of prognostic relevance. Additionally, correlation analysis of the relationship between RTKs and ER suggests co-regulatory mechanisms that may have potential significance in new therapeutic approaches.
Insights
Triple-negative breast cancer (TNBC) can be classified into two subtypes based on receptor tyrosine kinase (RTK) gene expression, distinguishing RTK-high and RTK-low profiles. This classification, particularly involving HER4, IGF-1R, and IGF-2R, shows prognostic relevance and potential for targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 expression, limiting targeted treatment options.
- TNBC represents a heterogeneous group, necessitating novel stratification methods for personalized therapy.
- Identifying specific molecular profiles within TNBC is crucial for developing targeted treatment strategies.
Purpose of the Study:
- To identify receptor tyrosine kinase (RTK) profiles for patient stratification in TNBC.
- To explore gene expression and protein expression of RTKs and downstream signaling biomarkers.
- To investigate the prognostic relevance of identified TNBC subtypes.
Main Methods:
- Gene expression profiling using RT-PCR on 29 TNBC cases.
- Analysis of 31 RTK-associated biomarkers, including EGF and IGF receptor families.
- Immunohistochemical (IHC) characterization of selected biomarkers at the protein level.
Main Results:
- Hierarchical clustering identified two distinct TNBC subgroups with significant gene expression differences in 16 biomarkers.
- RTKs HER4, IGF-1R, IGF-2R, and hormone receptors ER/PR were central to subgroup differentiation.
- RTK-high TNBC subtypes showed a 100% 3-year survival rate versus 60% for RTK-low subtypes (p=0.022).
Conclusions:
- Gene expression and IHC analyses reveal two distinct TNBC subtypes based on RTK profiles.
- HER4, IGF-1R, IGF-2R, ER, and PR are key biomarkers for TNBC subtyping and prognosis.
- RTK-high and RTK-low TNBC signatures possess prognostic relevance, suggesting potential for targeted therapeutic approaches.
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