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Updated: Feb 23, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities
Nathan J Lanning1, Joshua P Castle2, Simar J Singh3
1California State University, Los Angeles, 5151 State University Drive, Los Angeles, CA 90032 USA.
Background:
Among breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities.
Methods:
We quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects.
Results:
TNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases.
Conclusions:
Similar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients.
Insights
Triple-negative breast cancer (TNBC) exhibits metabolic heterogeneity. Targeting metabolic pathways sensitizes TNBC to receptor tyrosine kinase inhibitors, offering new therapeutic strategies for this aggressive cancer.
Area of Science:
- Biochemistry
- Oncology
- Systems Biology
Background:
- Triple-negative breast cancer (TNBC) has a poor prognosis and lacks targeted therapies.
- Receptor tyrosine kinases (RTKs) like EGFR and MET are highly expressed in TNBC.
- RTK signaling alters cancer cell metabolism, presenting therapeutic opportunities.
Purpose of the Study:
- To investigate the metabolic profiles of TNBC subtypes.
- To determine the response of TNBC cells to RTK inhibitors and metabolic pathway modulators.
- To identify metabolic vulnerabilities that sensitize TNBC to targeted therapies.
Main Methods:
- Metabolic profiling of TNBC cell lines using gas chromatography-mass spectrometry.
- Metabolic flux analysis to assess glycolytic and oxidative rates.
- Screening with RTK inhibitors (MET and EGFR) and metabolic pathway modulators, including siRNA screens.
Main Results:
- Significant metabolic heterogeneity was observed across TNBC cell line models.
- A core set of TCA cycle and fatty acid pathways were identified.
- Perturbation of these metabolic pathways sensitized TNBC cells to RTK inhibitors.
Conclusions:
- TNBC subtypes display distinct metabolic profiles and drug responses.
- Understanding metabolic vulnerabilities can guide targeted therapy for TNBC.
- Targeting metabolic pathways alongside RTK inhibition shows promise for TNBC treatment.
