Abstract
The recurrence of breast cancer in patients is a persistent challenge to the medical fraternity. Breast tumor contains a small population of cells with high tumor initiating and metastatic potential, known as cancer stem cells (CSCs), which are resistant to existing chemotherapeutics. CSCs contribute to the aggressiveness of triple negative breast cancers (TNBCs), thereby necessitating the identification of molecular targets on breast CSCs. TNBC cell line MDA-MB-231, in comparison with MCF-7, demonstrated a higher expression of epidermal growth factor receptor (EGFR). Thus, the naturally occurring flavanone, chrysin, with limited potential as a chemotherapeutic agent, was structurally modified by designing an analog with EGFR binding affinity using a molecular docking approach and subsequently synthesised. Chrysin analog CHM-09 and known EGFR inhibitors demonstrated a comparable anti-proliferative, anti-migratory activity along with the induction of apoptosis and cell cycle arrest in MDA-MB-231. Furthermore, sorted CD24−/CD44+-breast CSCs and CD24+-breast cancer cells from MDA-MB-231 demonstrated a markedly high expression of EGFR in the former than in the latter. CHM-09 and EGFR inhibitors could perturb EGF-induced EGFR signalling of breast CSC proliferation, migration, mammosphere formation and mesenchymal tri-lineage differentiation. CHM-09 or EGFR inhibitors not only led to inactivation of EGFR downstream signalling pathways such as Akt, extracellular signal regulated kinase and signal transducer and activator of transcription 3, but also induction of mesenchymal–epithelial transition as confirmed by decreased N-cadherin and increased E-cadherin expression. Finally, combinatorial treatment of EGFR inhibitors and doxorubicin led to significant increase in breast CSCs responsiveness to a chemotherapeutic drug. The results of the present study suggest that EGFR is a therapeutic target in breast CSCs and that abrogation of EGFR signalling along with chemotherapeutic drugs is an effective approach against breast cancer.
Original language | English (US) |
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Pages (from-to) | 1830-1854 |
Number of pages | 25 |
Journal | FEBS Journal |
Volume | 284 |
Issue number | 12 |
DOIs | |
State | Published - Jun 1 2017 |
Externally published | Yes |
Bibliographical note
Funding Information:AD acknowledges the funding provided by DBT, Government of India, Cancer Pilot Project ‘GAP-0514, Grant Sanction No. 6242-P65/RGCB/PMD/DBT/AMTD/2015’ and CSIR, Ministry of Science and Technology, Government of India, XIIth Five-year Plan Project #CSC-0111. SD acknowledges the funding provided by DBT, Government of India, F. No. BT/327/NE/TBP/2012. Fellowships provided by DBT, ICMR and CSIR are gratefully acknowledged by KM (DBT-SRF), ND (ICMR-SRF) and RY (CSIR-JRF). We also acknowledge the technical assistance provided by Mr Suresh Y. with respect to the flow cytometric analysis and confocal imaging at CSIR-IICT. This work has pending patent application.
Publisher Copyright:
© 2017 Federation of European Biochemical Societies
Keywords
- CD24/CD44-breast CSCs
- chemoresponsiveness
- epidermal growth factor receptor
- mammospheres
- mesenchymal–epithelial transition