Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth.
Notch functions as an oncogene or tumor inhibitor in various cancers, and decreases in Notch2 expression are associated with increasing grade of human breast cancer. We constitutively activated Notch signaling with intracellular domain (ICD) expression in the human adenocarcinoma line MDA-MB-231. Notch2 signaling increased apoptosis, whereas Notch4ICD (int3) significantly increased cell proliferation and growth. Cells with activated Notch2 or Notch4 were injected into nu/nu mice for analysis of in vivo tumor xenograft phenotype. Tumor growth was significantly altered depending on the receptor activated. Notch2ICD potently suppressed tumor take and growth, leading to a 60% decrease in tumors and significantly smaller, necrotic tumors. Despite this, Notch2ICD tumors were highly vascularized, although the vessels were smaller and comprised a more immature network compared with Notch4ICD tumors. Notch4ICD tumors were highly aggressive and well vascularized, indicating a role for Notch4 signaling in the promotion of the malignant phenotype in addition to its transforming ability. Although both NotchICD groups expressed angiogenic factors, Notch4ICD had selective vascular endothelial growth factor-D in both tumor and host stroma, suggesting a differential regulation of cytokines that may impact vascular recruitment and autocrine tumor signaling. Our results demonstrate that Notch2 signaling is a potent inhibitory signal in human breast cancer xenografts.
Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Dr., Scarborough, ME 04076, USA.
Christine F
CF
O'Neill
Sumithra
S
Urs
Christina
C
Cinelli
Alexis
A
Lincoln
Robert J
RJ
Nadeau
Ruth
R
León
Jessica
J
Toher
Carla
C
Mouta-Bellum
Robert E
RE
Friesel
Lucy
L
Liaw
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014183:Transplantation, Heterologous / Q000473:pathology / Q000502:physiology
C497764:NOTCH2 protein, human; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D051883:Receptor, Notch2; D000074562:Receptor, Notch4; D051880:Receptors, Notch