Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor.

2.50
Hdl Handle:
http://hdl.handle.net/10541/109287
Title:
Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor.
Authors:
Harrison, Hannah; Farnie, Gillian; Howell, Sacha J ( 0000-0001-8141-6515 ) ; Rock, Rebecca E; Stylianou, Spyros; Brennan, Keith; Bundred, Nigel J; Clarke, Robert B
Abstract:
Notch receptor signaling pathways play an important role not only in normal breast development but also in breast cancer development and progression. We assessed the role of Notch receptors in stem cell activity in breast cancer cell lines and nine primary human tumor samples. Stem cells were enriched by selection of anoikis-resistant cells or cells expressing the membrane phenotype ESA(+)/CD44(+)/CD24(low). Using these breast cancer stem cell populations, we compared the activation status of Notch receptors with the status in luminally differentiated cells, and we evaluated the consequences of pathway inhibition in vitro and in vivo. We found that Notch4 signaling activity was 8-fold higher in stem cell-enriched cell populations compared with differentiated cells, whereas Notch1 signaling activity was 4-fold lower in the stem cell-enriched cell populations. Pharmacologic or genetic inhibition of Notch1 or Notch4 reduced stem cell activity in vitro and reduced tumor formation in vivo, but Notch4 inhibition produced a more robust effect with a complete inhibition of tumor initiation observed. Our findings suggest that Notch4-targeted therapies will be more effective than targeting Notch1 in suppressing breast cancer recurrence, as it is initiated by breast cancer stem cells.
Affiliation:
Breast Biology Group, School of Cancer, Enabling Sciences and Technology, Paterson Institute for Cancer Research, University of Manchester, Manchester Academic Health Sciences Centre, The Christie NHS Foundation Trust; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom.
Citation:
Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. 2010, 70 (2):709-18 Cancer Res.
Journal:
Cancer Research
Issue Date:
15-Jan-2010
URI:
http://hdl.handle.net/10541/109287
DOI:
10.1158/0008-5472.CAN-09-1681
PubMed ID:
20068161
Type:
Article
Language:
en
ISSN:
1538-7445
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research; Medical Oncology

Full metadata record

DC FieldValue Language
dc.contributor.authorHarrison, Hannahen
dc.contributor.authorFarnie, Gillianen
dc.contributor.authorHowell, Sacha Jen
dc.contributor.authorRock, Rebecca Een
dc.contributor.authorStylianou, Spyrosen
dc.contributor.authorBrennan, Keithen
dc.contributor.authorBundred, Nigel Jen
dc.contributor.authorClarke, Robert Ben
dc.date.accessioned2010-08-09T12:49:36Z-
dc.date.available2010-08-09T12:49:36Z-
dc.date.issued2010-01-15-
dc.identifier.citationRegulation of breast cancer stem cell activity by signaling through the Notch4 receptor. 2010, 70 (2):709-18 Cancer Res.en
dc.identifier.issn1538-7445-
dc.identifier.pmid20068161-
dc.identifier.doi10.1158/0008-5472.CAN-09-1681-
dc.identifier.urihttp://hdl.handle.net/10541/109287-
dc.description.abstractNotch receptor signaling pathways play an important role not only in normal breast development but also in breast cancer development and progression. We assessed the role of Notch receptors in stem cell activity in breast cancer cell lines and nine primary human tumor samples. Stem cells were enriched by selection of anoikis-resistant cells or cells expressing the membrane phenotype ESA(+)/CD44(+)/CD24(low). Using these breast cancer stem cell populations, we compared the activation status of Notch receptors with the status in luminally differentiated cells, and we evaluated the consequences of pathway inhibition in vitro and in vivo. We found that Notch4 signaling activity was 8-fold higher in stem cell-enriched cell populations compared with differentiated cells, whereas Notch1 signaling activity was 4-fold lower in the stem cell-enriched cell populations. Pharmacologic or genetic inhibition of Notch1 or Notch4 reduced stem cell activity in vitro and reduced tumor formation in vivo, but Notch4 inhibition produced a more robust effect with a complete inhibition of tumor initiation observed. Our findings suggest that Notch4-targeted therapies will be more effective than targeting Notch1 in suppressing breast cancer recurrence, as it is initiated by breast cancer stem cells.en
dc.language.isoenen
dc.subjectBreast Canceren
dc.subjectTumour Cell Lineen
dc.subjectCancerous Stem Cellsen
dc.subject.meshAnimals-
dc.subject.meshAntigens, CD24-
dc.subject.meshAntigens, CD44-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCell Line, Tumor-
dc.subject.meshHumans-
dc.subject.meshMembrane Proteins-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshMice, Nude-
dc.subject.meshNeoplastic Stem Cells-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshReceptor, Notch1-
dc.subject.meshReceptors, Notch-
dc.subject.meshSignal Transduction-
dc.titleRegulation of breast cancer stem cell activity by signaling through the Notch4 receptor.en
dc.typeArticleen
dc.contributor.departmentBreast Biology Group, School of Cancer, Enabling Sciences and Technology, Paterson Institute for Cancer Research, University of Manchester, Manchester Academic Health Sciences Centre, The Christie NHS Foundation Trust; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom.en
dc.identifier.journalCancer Researchen

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