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Time-lapse Imaging of Primary Preneoplastic Mammary Epithelial Cells Derived from Genetically Engineered Mouse Models of Breast Cancer
Published on: February 8, 2013
Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1
Mollie H Wright1, Ana I Robles, Jason I Herschkowitz
1Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA. molliewright@gmail.com
Background:
Development of therapies for patients with BRCA1 mutations has been hampered by lack of readily available in vitro and in vivo models. We recently showed that transplantation of transgenic mammary tumors as cell suspensions into naïve recipients generates reproducible tumors with remarkable stability of gene expression profile. We examined the expression profiles of original and serially transplanted mammary tumors from Brca1 deficient mice, and tumor derived cell lines to validate their use for preclinical testing and studies of tumor biology.
Methods:
Original tumors, serially transplanted and multiple cell lines derived from Brca1 mammary tumors were characterized by morphology, gene and protein expression, and cell surface markers.
Results:
Gene expression among Brca1 tumors showed more heterogeneity than among previously characterized tumors from MMTV-PyMT and -Wnt1 models. Gene expression data segregated Brca1 tumors into 3 distinct types: basal, mixed luminal, and tumors with epithelial-to-mesenchymal transition (EMT). Serial transplantation of individual tumors and multiple cell lines derived from the original tumors recapitulated the molecular characteristics of each tumor of origin. One tumor had distinct features of EMT and gave rise to cell lines that contained a distinct CD44+/CD24-/low population that may correlate with human breast cancer stem cells.
Conclusion:
Although individual tumors expanded by transplantation maintain the genomic profile of the original tumors, the heterogeneity among Brca1 tumors limits the extent of their use for preclinical testing. However, cell lines offer a robust material for understanding tumor biology and response to therapies driven by BRCA1 deficiency.
Insights
Developing therapies for BRCA1 mutations is challenging due to limited models. This study validates using transplanted Brca1 mouse tumors and derived cell lines for preclinical research and tumor biology studies.
Area of Science:
- Oncology
- Genetics
- Translational Research
Background:
- Therapeutic development for BRCA1-mutated cancers is hindered by a lack of suitable in vitro and in vivo models.
- Previous work demonstrated reproducible tumor generation via transplantation of transgenic mammary tumors.
- This study validates Brca1-deficient mouse mammary tumors and derived cell lines for preclinical applications.
Purpose of the Study:
- To examine the expression profiles of original and serially transplanted Brca1-deficient mouse mammary tumors.
- To validate the utility of these models for preclinical testing and tumor biology research.
- To assess the stability of gene expression profiles during serial transplantation and cell line derivation.
Main Methods:
- Characterization of original tumors, serially transplanted tumors, and derived cell lines using morphology, gene and protein expression, and cell surface markers.
- Comparative gene expression analysis of Brca1 tumors against MMTV-PyMT and -Wnt1 models.
- Identification of distinct tumor subtypes based on gene expression patterns.
Main Results:
- Brca1 tumors exhibited greater gene expression heterogeneity compared to MMTV-PyMT and -Wnt1 models.
- Gene expression data classified Brca1 tumors into basal, mixed luminal, and epithelial-to-mesenchymal transition (EMT) types.
- Serial transplantation and cell line derivation maintained the molecular characteristics of the original tumors.
- A specific EMT-featured tumor yielded cell lines with a CD44+/CD24-/low population, potentially correlating with human breast cancer stem cells.
Conclusions:
- While transplanted tumors retain genomic profiles, Brca1 tumor heterogeneity limits their broad preclinical utility.
- Derived cell lines provide a robust platform for investigating BRCA1-deficient tumor biology and therapeutic responses.
- These models offer valuable insights into the complexities of BRCA1-associated cancers.
