title: Essential role of Notch4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer.
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.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Quyen Thu
authors.initials: QT
authors.lastname: Bui
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Im
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Sung Baek
authors.initials: SB
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Hanyang University, Ansan 15588, Republic of Korea.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea.
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Lim
authors.affiliation: College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Republic of Korea.
authors.forename: Bumseok
authors.initials: B
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: kwkang@snu.ac.kr.
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D013629:Tamoxifen
keywords: Breast cancer; Metastasis; Notch4; STAT3; Tamoxifen resistance