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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
Aberrant activation of notch signaling in human breast cancer
Spyros Stylianou1, Rob B Clarke, Keith Brennan
1Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Christie Hospital NHS Trust, Manchester M13 9PT, United Kingdom.
Abstract:
A role for Notch signaling in human breast cancer has been suggested by both the development of adenocarcinomas in the murine mammary gland following pathway activation and the loss of Numb expression, a negative regulator of the Notch pathway, in a large proportion of breast carcinomas. However, it is not clear currently whether Notch signaling is frequently activated in breast tumors, and how it causes cellular transformation. Here, we show accumulation of the intracellular domain of Notch1 and hence increased Notch signaling in a wide variety of human breast carcinomas. In addition, we show that increased RBP-Jkappa-dependent Notch signaling is sufficient to transform normal breast epithelial cells and that the mechanism of transformation is most likely through the suppression of apoptosis. More significantly, we show that attenuation of Notch signaling reverts the transformed phenotype of human breast cancer cell lines, suggesting that inhibition of Notch signaling may be a therapeutic strategy for this disease.
Insights
Notch signaling is frequently activated in human breast cancer, promoting tumor growth by suppressing apoptosis. Inhibiting this pathway may offer a new therapeutic strategy for breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Signaling
Background:
- Notch signaling's role in breast cancer is suggested by murine models and Numb expression loss in human carcinomas.
- The precise frequency and mechanism of Notch pathway activation in human breast tumors remain unclear.
Purpose of the Study:
- To investigate the prevalence of Notch signaling activation in human breast carcinomas.
- To elucidate the mechanism by which Notch signaling contributes to cellular transformation in breast cancer.
- To evaluate the therapeutic potential of inhibiting Notch signaling in breast cancer.
Main Methods:
- Detection of intracellular Notch1 domain accumulation in human breast carcinomas.
- Assessment of RBP-Jkappa-dependent Notch signaling in normal breast epithelial cell transformation.
- Evaluation of Notch signaling attenuation effects on transformed human breast cancer cell lines.
Main Results:
- Increased Notch signaling, indicated by intracellular Notch1 domain accumulation, was observed in diverse human breast carcinomas.
- Activated RBP-Jkappa-dependent Notch signaling induced transformation of normal breast epithelial cells, likely via apoptosis suppression.
- Reducing Notch signaling reversed the transformed phenotype in human breast cancer cell lines.
Conclusions:
- Notch signaling is frequently activated in human breast cancer.
- This activation contributes to tumorigenesis, potentially by inhibiting apoptosis.
- Targeting Notch signaling presents a promising therapeutic avenue for breast cancer.
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