Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor.
Howell, Sacha J
Rock, Rebecca E
Bundred, Nigel J
Clarke, Robert B
AffiliationBreast 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.
MetadataShow full item record
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.
CitationRegulation of breast cancer stem cell activity by signaling through the Notch4 receptor. 2010, 70 (2):709-18 Cancer Res.
- Notch4 Signaling Confers Susceptibility to TRAIL-Induced Apoptosis in Breast Cancer Cells.
- Authors: Naik S, MacFarlane M, Sarin A
- Issue date: 2015 Jul
- Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.
- Authors: Simões BM, O'Brien CS, Eyre R, Silva A, Yu L, Sarmiento-Castro A, Alférez DG, Spence K, Santiago-Gómez A, Chemi F, Acar A, Gandhi A, Howell A, Brennan K, Rydén L, Catalano S, Andó S, Gee J, Ucar A, Sims AH, Marangoni E, Farnie G, Landberg G, Howell SJ, Clarke RB
- Issue date: 2015 Sep 29
- Essential role of Notch4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer.
- Authors: Bui QT, Im JH, Jeong SB, Kim YM, Lim SC, Kim B, Kang KW
- Issue date: 2017 Apr 1
- Notch1 inhibition alters the CD44hi/CD24lo population and reduces the formation of brain metastases from breast cancer.
- Authors: McGowan PM, Simedrea C, Ribot EJ, Foster PJ, Palmieri D, Steeg PS, Allan AL, Chambers AF
- Issue date: 2011 Jul
- Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells.
- Authors: Lombardo Y, Faronato M, Filipovic A, Vircillo V, Magnani L, Coombes RC
- Issue date: 2014 Jun 11