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TOMM40/FADS2 Expression Ratio Predicts the Sensitivity to mTOR Inhibitors in Triple-Negative Breast Cancer
Salman Mohamed Farah1, Jing-Quan Zheng2,3,4, Leon Tsung-Ju Lee2,5,6
1International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Background:
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). There is a lack of predictive biomarkers for the response of patients with TNBC to targeted therapies.
Methods:
Bioinformatics analysis was conducted to generate differentially expressed genes (DEGs) of the mammalian target of rapamycin complex 1 (MTORC1) gene set between normal tissues and primary tumors derived from TNBC patients using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Cox regression analysis was performed to identify independent prognostic factors. Endogenous expression levels of the identified prognostic genes were detected in a panel of TNBC cell lines and breast cancer tissues using western blotting and immunohistochemistry (IHC).
Results:
Our findings revealed two prognostic genes: FADS2 and TOMM40. TOMM40 (HR = 2.243) was a risk factor and FADS2 was a protective factor (HR = 0.652). A higher TOMM40/FADS2 ratio is associated with poor outcomes in patients with TNBC. The TOMM40/FADS2 ratio was significantly (p < 0.05) associated with age, tumor size, lymph node metastasis, pathologic stage, and overall survival of patients with TNBC. Remarkably, the MTT cytotoxicity assay revealed that TNBC cells, which possess a higher TOMM40/FADS2 ratio than TNBC cells with a lower TOMM40/FADS2 ratio, are more sensitive to mammalian target of rapamycin (mTOR) inhibitor treatment.
Conclusion:
Our results provide a new therapeutic strategy using the TOMM40/FADS2 expression ratio to predict the cellular sensitivity to mTOR inhibitor treatment in TNBC.
Insights
The TOMM40/FADS2 ratio can predict triple-negative breast cancer (TNBC) patient response to mTOR inhibitors. A higher ratio indicates greater sensitivity, offering a new therapeutic strategy for TNBC treatment.
Area of Science:
- Oncology
- Genomics
- Biomarker Discovery
Background:
- Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 expression.
- TNBC presents a challenge due to limited predictive biomarkers for targeted therapies.
Purpose of the Study:
- Identify novel predictive biomarkers for TNBC treatment response.
- Investigate the role of MTORC1 pathway genes in TNBC prognosis.
Main Methods:
- Bioinformatics analysis of TCGA and GEO databases for DEGs in MTORC1 pathway.
- Cox regression for prognostic factor identification.
- Western blotting and IHC for gene expression validation.
Main Results:
- Identified FADS2 (protective) and TOMM40 (risk) as prognostic genes.
- A higher TOMM40/FADS2 ratio correlates with poor TNBC outcomes and advanced stage.
- TNBC cells with higher TOMM40/FADS2 ratios show increased sensitivity to mTOR inhibitors.
Conclusions:
- The TOMM40/FADS2 ratio serves as a predictive biomarker for TNBC sensitivity to mTOR inhibitors.
- This ratio offers a potential new therapeutic strategy for TNBC management.
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