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Inhibiting epidermal growth factor receptor signalling potentiates mesenchymal–epithelial transition of breast cancer stem cells and their responsiveness to anticancer drugs
Author(s) -
Manupati Kanakaraju,
Dhoke Neha R.,
Debnath Tanusree,
Yeeravalli Ragini,
Guguloth Kalpana,
Saeidpour Shahrzad,
De Utpal Chandra,
Debnath Sudhan,
Das Amitava
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14084
Subject(s) - cancer research , cd44 , epidermal growth factor receptor , cancer stem cell , epithelial–mesenchymal transition , breast cancer , protein kinase b , population , biology , chemistry , stem cell , cancer , medicine , signal transduction , cell , microbiology and biotechnology , metastasis , genetics , environmental health
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 ( CSC s), which are resistant to existing chemotherapeutics. CSC s contribute to the aggressiveness of triple negative breast cancers ( TNBC s), thereby necessitating the identification of molecular targets on breast CSC s. 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 CD 24 − / CD 44 + ‐breast CSC s and CD 24 + ‐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 CSC s responsiveness to a chemotherapeutic drug. The results of the present study suggest that EGFR is a therapeutic target in breast CSC s and that abrogation of EGFR signalling along with chemotherapeutic drugs is an effective approach against breast cancer.