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Haploinsufficiency for p190B RhoGAP inhibits MMTV-Neu tumor progression
Brandy M Heckman-Stoddard1, Tracy Vargo-Gogola, Peter R McHenry
1Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. bheckmanstoddard@gmail.com
Introduction:
Rho signaling regulates key cellular processes including proliferation, survival, and migration, and it has been implicated in the development of many types of cancer including breast cancer. P190B Rho GTPase activating protein (RhoGAP) functions as a major inhibitor of the Rho GTPases. P190B is required for mammary gland morphogenesis, and overexpression of p190B in the mammary gland induces hyperplastic lesions. Hence, we hypothesized that p190B may play a pivotal role in mammary tumorigenesis.
Methods:
To investigate the effects of loss of p190B function on mammary tumor progression, p190B heterozygous mice were crossed with an MMTV-Neu breast cancer model. Effects of p190B deficiency on tumor latency, multiplicity, growth, preneoplastic progression and metastasis were evaluated. To investigate potential differences in tumor angiogenesis between the two groups, immunohistochemistry to detect von Willebrand factor was performed and quantified. To examine gene expression of potential mediators of the angiogenic switch, an angiogenesis PCR array was utilized and results were confirmed using immunohistochemistry. Finally, reciprocal transplantation of tumor fragments was performed to determine the impact of stromal deficiency of p190B on tumor angiogenesis.
Results:
P190B deficiency reduced tumor penetrance (53% of p190B+/-Neu mice vs. 100% of p190B+/+Neu mice formed tumors) and markedly delayed tumor onset by an average of 46 weeks. Tumor multiplicity was also decreased, but an increase in the number of preneoplastic lesions was detected indicating that p190B deficiency inhibited preneoplastic progression. Angiogenesis was decreased in the p190B heterozygous tumors, and expression of a potent angiogenic inhibitor, thrombospondin-1, was elevated in p190B+/-Neu mammary glands. Transplantation of p190B+/-Neu tumor fragments into wild-type recipients restored tumor angiogenesis. Strikingly, p190B+/+Neu tumor fragments were unable to grow when transplanted into p190B+/-Neu recipients.
Conclusions:
These data suggest that p190B haploinsufficiency in the epithelium inhibits MMTV-Neu tumor initiation. Furthermore, p190B deficiency in the vasculature is responsible, in part, for the inhibition of MMTV-Neu tumor progression.
Insights
Loss of p190B Rho GTPase activating protein (RhoGAP) function in mice significantly delayed breast cancer onset and progression. P190B deficiency in both tumor cells and blood vessels inhibits mammary tumor growth and metastasis.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Rho signaling is crucial for cellular processes like proliferation and migration, and is implicated in breast cancer development.
- P190B Rho GTPase activating protein (RhoGAP) is a key inhibitor of Rho GTPases and is essential for mammary gland development.
- Overexpression of p190B can lead to mammary gland hyperplastic lesions, suggesting its role in tumorigenesis.
Purpose of the Study:
- To investigate the role of p190B in mammary tumorigenesis.
- To determine the effects of p190B deficiency on breast cancer initiation, progression, and metastasis.
- To evaluate the impact of p190B on tumor angiogenesis.
Main Methods:
- Crossed p190B heterozygous mice with an MMTV-Neu breast cancer model.
- Assessed tumor latency, multiplicity, growth, preneoplastic progression, and metastasis.
- Utilized immunohistochemistry for von Willebrand factor and angiogenesis PCR arrays to study tumor angiogenesis.
- Performed reciprocal tumor fragment transplantation to assess stromal effects.
Main Results:
- P190B deficiency reduced tumor penetrance and delayed tumor onset by an average of 46 weeks.
- Tumor multiplicity decreased, while preneoplastic lesions increased, indicating inhibited progression.
- Angiogenesis was reduced in p190B-deficient tumors, with elevated thrombospondin-1 expression.
- Transplantation studies revealed p190B deficiency in vasculature partially inhibits tumor progression.
Conclusions:
- P190B haploinsufficiency in the epithelium inhibits MMTV-Neu tumor initiation.
- P190B deficiency in the vasculature contributes to the inhibition of MMTV-Neu tumor progression.
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