| The epidermal growth factor receptor (EGFR) belongs to the erbB family of receptor tyrosine kinases. Upon ligand binding, the EGFR is capable of dimerization and propagates signals regulating cell growth, migration and survival. Dysregulation of the EGFR is important for development and progression of different types of cancers, including breast cancer.;EGFR overexpression has been observed in more than 50% of triple negative breast cancer (TNBC), which is a more aggressive type of breast cancer and lacks effective therapies. Targeted therapy against EGFR has been used in TNBC. However, limited efficacy has been observed due to resistant mechanisms. In order to overcome this issue, we have developed two novel therapeutic peptides derived from the nuclear localization signal (NLS) sequence and juxtamembrane domain of EGFR and investigated their efficacy in regard to inhibiting EGFR translocation and activation in TNBC.;EGFR has been found to translocate into the nucleus and nuclear EGFR can affect cell proliferation, stress response and DNA repair through interacting with different components in the nucleus. Importantly, these functions of nuclear EGFR correlate with cancer prognosis and therapeutic resistance. We found that an EGFR NLS-derived peptide (ENLS peptide) could inhibit nuclear translocation of EGFR. We also showed that the ENLS peptide sensitized breast cancer cells to AG1478 (EGFR tyrosine kinase inhibitor) treatment.;The juxtamembrane domain of EGFR regulates its trafficking, interaction with calmodulin, and dimerization. These non-traditional kinase related functions of EGFR represent a novel target for EGFR therapy. We found that a mimetic peptide of the juxtamembrane domain of EGFR (EJ1 peptide) could effectively inhibit EGFR activation through promoting inactive dimer formation. It could also effectively kill cancer cells through processes of apoptosis and necrosis. Mechanistically, the EJ1 peptide affects membrane integrity thereby leading to calcium influx, disruption of mitochondrial membrane potential and reactive oxygen species accumulation. Importantly, EJ1 peptide appeared to be effective in inhibition of tumor growth and metastasis in a transgenic mouse model of breast cancer and showed no observable toxicity.;In conclusion, we demonstrated that two EGFR-derived peptides, working through novel strategies, represent a new foundation of effective therapeutic agents to breast cancer. |
