Essential role of Notch4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer

• Published in: Cancer letters Vol. 390; pp. 115 - 125
• Main Authors: Bui, Quyen Thu, Im, Ji Hye, Jeong, Sung Baek, Kim, Young-Mi, Lim, Sung Chul, Kim, Bumseok, Kang, Keon Wook
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.04.2017; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Hormonal - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - physiopathology; Cell adhesion & migration; Cell Line, Tumor; Cell Proliferation; Conflicts of interest; Drug Resistance, Neoplasm - genetics; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - physiology; Female; Fluorides; Genes; Genotype & phenotype; Hematology, Oncology and Palliative Medicine; Humans; Immunoblotting; Immunoglobulins; Kinases; Ligands; Metastasis; Mice, Nude; Notch4; Phosphorylation; Polymerase Chain Reaction; Protein Binding; Proteins; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Receptor, Notch4; Receptors, Notch - antagonists & inhibitors; Receptors, Notch - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; STAT3; STAT3 Transcription Factor - metabolism; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; Tamoxifen resistance; Nuclear factor-kappa B; Estrogen receptor; TAM; Polyethylene glycol 400; AP-1; Tamoxifen resistance; metastasis; Signal transducer and activator of transcription 3; Intracellular domain; Matrix metalloproteinase 2; cancer stem cells; DAPT; tamoxifen; CSCs; N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; MMP2; STAT3; breast cancer; ICD; EMT; ER; PEG 400; Notch4; Epithelial-mesenchymal transition; Activator protein-1; NF-?B; Breast cancer; Metastasis; NF-ĸB
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.01.014

Abstract We previously demonstrated that tamoxifen (TAM)-resistant human breast cancer (TAMR-MCF-7) cells showed increased expression of mesenchymal marker proteins compared to the parent MCF-7 cells. Notch is functionally important in the promotion of epithelial-mesenchymal transition (EMT) during both development and tumor progression. Notch1 and Notch4 have been reported as prognostic markers in human breast cancer. Here, we indicated that Notch4, but not Notch1, plays a critical role in the regulation of EMT signaling in TAMR-MCF-7 cells. Notch4 suppression by either Notch inhibitors or Notch4 siRNA attenuated EMT signaling. Tyrosine-phosphorylated STAT3 protein is known as a crucial signaling molecule in the regulation of tumorigenesis and metastasis. We found that TAMR-MCF-7 cells exhibited constitutive STAT3 phosphorylation, and Notch inhibition reduced the level of activated STAT3 in TAMR-MCF-7 cells. An intrasplenic injection model of liver metastases was performed using TAMR-MCF-7 cells. Mice injected with N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, 10 mg/kg) formed smaller splenic tumors and showed a reduced micrometastatic tumor burden in their livers compared with the control group treated with vehicle. To conclude, Notch4 could be a potential target to prevent metastasis in TAM-resistant breast cancer.