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Somatic mutations that contribute to breast cancer
1Oncogenetics Section, National Cancer Institute, Bethesda, MD 20892, USA.
Biochemical Society Symposium
|March 26, 1998
Summary
Researchers identified two genes, NOTCH4/INT3 and INT6, involved in mouse mammary tumorigenesis. MMTV integration into NOTCH4/INT3 causes gain-of-function mutations, while INT6 mutations lead to dominant-negative effects or altered function, impacting breast cancer development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Loss of heterozygosity (LOH) on chromosome 17q is observed in human breast carcinomas, suggesting tumor suppressor genes.
- The mouse mammary tumor model system is used to identify genes involved in mammary tumorigenesis through viral integration.
Purpose of the Study:
- To identify genes contributing to mammary tumorigenesis via mouse mammary tumor virus (MMTV) integration.
- To investigate the role of NOTCH4/INT3 and INT6 in mammary gland development and cancer.
Main Methods:
- Cytogenetic and molecular analyses of human breast carcinomas.
- Physical mapping of chromosome 17q21.
- Utilizing the mouse mammary tumor model system with MMTV integration.
- Gene sequencing and analysis of viral-host interactions.
Main Results:
- Identified NOTCH4/INT3 and INT6 as genes affected by MMTV integration in mammary tumors.
- MMTV interruption of NOTCH4/INT3 resulted in gain-of-function mutations impacting mammary development and tumorigenesis.
- MMTV integration into INT6 led to truncated chimaeric RNA, suggesting dominant-negative or altered function mutations.
Conclusions:
- NOTCH4/INT3 and INT6 are key players in MMTV-induced mammary tumorigenesis.
- MMTV integration can cause gain-of-function or dominant-negative mutations in critical genes.
- Further investigation into INT6's novel sequence and evolutionary conservation is warranted.