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Oncogenic suppression of apoptosis uncovers a Rac1/JNK proliferation pathway activated by loss of Par3
A Archibald1, C Mihai1, I G Macara2
1Goodman Cancer Research Centre, Department of Oncology, McGill University, Montreal, Quebec, Canada.
Abstract:
Disruption of epithelial organization and loss of growth control are universal features of carcinomas, yet how these features are linked during cancer progression remains poorly understood. Cell polarity proteins control cellular and tissue organization and are emerging as important mediators of cancer progression. The Par3 polarity protein is a molecular scaffold that functions to recruit and spatially organize signaling factors, and was recently identified as a suppressor of breast cancer invasion and metastasis. Here, we show that loss of Par3 in mammary epithelial cells promotes apoptosis, and that oncogenic Notch overcomes the apoptotic signal to reveal an unexpected pro-proliferative role for loss of Par3 in mammary tumors. In this context, loss of Par3 deregulates Rac1 activity to activate Jun N-terminal Kinase-dependent proliferation and tumor growth. Thus, we demonstrate a mechanism by which loss of Par3 promotes proliferation and tumorigenesis, which supports a tumor-suppressive function for Par3 in the mammary epithelium.
Insights
Loss of the Par3 polarity protein in mammary cells initially causes cell death but can paradoxically promote tumor growth. This occurs through deregulation of Rac1 activity, leading to Jun N-terminal Kinase-dependent proliferation.
Area of Science:
- Cell biology
- Cancer research
- Molecular oncology
Background:
- Carcinomas exhibit disrupted epithelial organization and uncontrolled growth.
- Cell polarity proteins, like Par3, are crucial for tissue organization and cancer progression.
- Par3 acts as a scaffold, organizing signaling factors, and suppresses breast cancer invasion.
Purpose of the Study:
- To investigate the role of Par3 loss in mammary epithelial cells during cancer progression.
- To understand the link between disrupted cell polarity and tumor growth.
- To elucidate the mechanism by which Par3 loss influences proliferation and tumorigenesis.
Main Methods:
- Studied the effects of Par3 loss in mammary epithelial cells.
- Utilized oncogenic Notch signaling to overcome apoptotic signals.
- Investigated Rac1 activity and Jun N-terminal Kinase (JNK) signaling pathways.
Main Results:
- Loss of Par3 in mammary epithelial cells induces apoptosis.
- Oncogenic Notch signaling overrides apoptosis, revealing a pro-proliferative role for Par3 loss.
- Par3 loss deregulates Rac1 activity, activating JNK-dependent proliferation and tumor growth.
Conclusions:
- Loss of Par3 promotes proliferation and tumorigenesis in the mammary epithelium.
- Par3 functions as a tumor suppressor in the mammary epithelium.
- The findings reveal a novel mechanism linking cell polarity disruption to cancer progression.
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