Related Experiment Videos
The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. moynaham@mskcc.org
Abstract:
BRCA1 and BRCA2 mutations are estimated to be responsible for the great majority of familial breast and ovarian cancers. Much progress has been made toward the understanding of the function of these proteins through genetic, biochemical, and structural studies. The embryonic lethality encountered in the knockout mouse initially hindered the development of mouse models aimed at studying tumor suppression. However, mice that harbor hypomorphic Brca1 and Brca2 alleles and cre-mediated tissue-specific deletions for Brca1 and Brca2 have been generated. Mice deficient for either Brca1 or Brca2 sustain a wide range of carcinoma and mammary epithelium deleted for Brca1 or Brca2 is highly susceptible to mammary tumorigenesis. Mammary (and other) tumors occur at long latency as compared to oncogene-induced mouse tumors. p53 deficiency is highly cooperative with both Brca1 and Brca2 in promoting tumorigenesis. Analysis of Brca1-associated mammary tumors reveals significant similarities to BRCA1-associated breast cancer in regard to high tumor grade, hormone receptor negativity, a high incidence of p53 mutations and genetic instability.
Insights
BRCA1 and BRCA2 gene mutations drive most hereditary breast and ovarian cancers. Mouse models reveal these genes are crucial for tumor suppression, with deficiencies leading to various cancers, particularly in mammary tissue.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- BRCA1 and BRCA2 mutations are key drivers of familial breast and ovarian cancers.
- Understanding BRCA protein function is crucial for cancer research.
- Early mouse models faced challenges due to embryonic lethality.
Purpose of the Study:
- To investigate the role of Brca1 and Brca2 in tumor suppression using advanced mouse models.
- To analyze the susceptibility of mammary epithelium to tumorigenesis in the absence of functional Brca1 or Brca2.
- To explore the cooperative effects of p53 deficiency with Brca1 and Brca2 mutations on cancer development.
Main Methods:
- Generation of mice with hypomorphic Brca1/Brca2 alleles.
- Utilizing cre-mediated tissue-specific deletions for Brca1 and Brca2.
- Comparative analysis of tumor latency and characteristics in deficient mice versus oncogene-induced models.
- Investigating the impact of p53 deficiency in Brca1/Brca2-deficient mice.
Main Results:
- Mice deficient for Brca1 or Brca2 developed a range of carcinomas.
- Mammary epithelium lacking Brca1 or Brca2 showed high susceptibility to mammary tumorigenesis.
- Tumors in these models developed with long latency.
- p53 deficiency significantly accelerated tumorigenesis in Brca1/Brca2-deficient mice.
- Brca1-associated mammary tumors mirrored human BRCA1-associated breast cancer features (high grade, hormone receptor negativity, p53 mutations, genetic instability).
Conclusions:
- Brca1 and Brca2 are critical tumor suppressors, particularly in mammary tissue.
- Developed mouse models are valuable for studying BRCA-related cancers.
- The findings highlight similarities between mouse models and human BRCA-associated cancers, aiding further research.