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Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Phyto-Sesquiterpene Lactones Prevent the Development of Multidrug Resistance in TNBC via ABC Transporters Inhibition
Ying-Tzu Chang1, I-Ting Wu1, Chien-Hsing Lee2,3,4
1Department of Pharmacy, College of Pharmacy, China Medical University, Taichung 406040, Taiwan.
Background:
Multidrug resistance (MDR) in triple-negative breast cancer (TNBC) leads to treatment failure and tumor recurrence. Dysregulation of the MYC oncogene is associated with the pathogenesis of TNBC and the development of chemoresistance via overexpression of ATP-binding cassette (ABC) transporters. Therefore, in the present study, we aimed to identify molecules from a natural product origin that prevent the development of MDR in TNBC by targeting the MYC signaling.
Methods:
The cell viability of TNBC was evaluated using sulforhodamine assay. Protein levels were detected by western blots or enzyme-linked immunosorbent assays. Intracellular calcein and hoechst33342 accumulation assay aimed to evaluate the inhibitory ability of phytocompounds on drug-efflux functions of ABCB1 and ABCG2 transporters. The Cancer Genome Atlas (TCGA) database was used to explore clinical genomic data. Furthermore, the zebrafish xenotransplantation model bearing Dil-labeled TNBC cells was applied to testify the in vivo effects of phyto-sesquiterpene lactones.
Results:
The results of the present study demonstrated that the phyto-sesquiterpene lactones exhibited an MDR prevention effect by repressing efflux activities of ABCB1 and ABCG2 transporters. Mechanistic studies showed that phyto-sesquiterpene lactones inducted TNBC cell apoptosis and cell cycle G2/M arrested by blocking the STAT3/MYC pathway. Clinical genomic data demonstrated that the percentages of MYC amplification and mRNA were upregulated approximately two-fold higher in the TNBC patients than the non-TNBC breast cancer patients. The survival of patients with an alteration in MYC was significantly lower in TNBC as compared to other subtypes. Moreover, the results of the zebrafish xenograft model confirmed that phyto-sesquiterpene lactones exerted stronger inhibitory effects on TNBC tumor growth in vivo.
Conclusions:
In conclusion, these three phyto-sesquiterpene lactones were promising candidates for TNBC treatment and shed light on the prevention of developing MDR TNBC.
Insights
Natural compounds called phyto-sesquiterpene lactones can prevent multidrug resistance (MDR) in triple-negative breast cancer (TNBC). These compounds target the MYC signaling pathway, offering a new strategy for TNBC treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) is a major challenge in triple-negative breast cancer (TNBC) treatment, leading to therapeutic failure and recurrence.
- The MYC oncogene is implicated in TNBC pathogenesis and chemoresistance, often through the overexpression of ATP-binding cassette (ABC) transporters.
- Targeting MYC signaling presents a potential strategy to overcome MDR in TNBC.
Purpose of the Study:
- To identify natural products that can prevent MDR development in TNBC.
- To investigate the mechanism by which these natural products target MYC signaling.
- To evaluate the efficacy of these compounds in preclinical models.
Main Methods:
- Sulforhodamine assays for cell viability and western blots/ELISAs for protein detection.
- Calcein and Hoechst 33342 accumulation assays to assess ABC transporter inhibition.
- TCGA database analysis for clinical genomic data and zebrafish xenotransplantation for in vivo efficacy.
Main Results:
- Phyto-sesquiterpene lactones inhibited MDR by repressing ABCB1 and ABCG2 transporter activity.
- These compounds induced apoptosis and G2/M cell cycle arrest in TNBC cells by blocking the STAT3/MYC pathway.
- Clinical data showed higher MYC amplification and mRNA levels in TNBC patients, correlating with poorer survival; zebrafish models confirmed in vivo tumor growth inhibition.
Conclusions:
- Three phyto-sesquiterpene lactones show promise for TNBC treatment.
- These compounds offer a potential strategy for preventing MDR in TNBC.
- Further investigation into these natural products could lead to novel therapeutic approaches for TNBC.
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