Ink4a/Arf(-/-) and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic
K Kai1, T Iwamoto2, T Kobayashi3
11] Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [3] Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
Abstract:
Intratumoral heterogeneity within individual breast tumors is a well-known phenomenon that may contribute to drug resistance. This heterogeneity is dependent on several factors, such as types of oncogenic drivers and tumor precursor cells. The purpose of our study was to engineer a mouse mammary tumor model with intratumoral heterogeneity by using defined genetic perturbations. To achieve this, we used mice with knockout (-/-) of Ink4a/Arf, a tumor suppressor locus; these mice are known to be susceptible to non-mammary tumors such as fibrosarcoma. To induce mammary tumors, we retrovirally introduced an oncogene, HRAS(G12V), into Ink4a/Arf(-/-) mammary cells in vitro, and those cells were inoculated into syngeneic mice mammary fat pads. We observed 100% tumorigenesis. The tumors formed were negative for estrogen receptor, progesterone receptor and HER2. Further, they had pathological features similar to those of human triple-negative breast cancer (TNBC) (for example, pushing borders, central necrosis). The tumors were found to be heterogeneous and included two subpopulations: CD49f(-) quiescent cells and CD49f(+)cells. Contrary to our expectation, CD49f(-) quiescent cells had high tumor-initiating potential and CD49f(+)cells had relatively low tumor-initiating potential. Gene expression analysis revealed that CD49f(-) quiescent cells overexpressed epithelial-to-mesenchymal transition-driving genes, reminiscent of tumor-initiating cells and claudin-low breast cancer. Our animal model with intratumoral heterogeneity, derived from defined genetic perturbations, allows us to test novel molecular targeted drugs in a setting that mimics the intratumoral heterogeneity of human TNBC.
Insights
Researchers engineered a mouse model of triple-negative breast cancer (TNBC) exhibiting intratumoral heterogeneity. This model, with distinct CD49f(-) and CD49f(+) cell populations, mimics human TNBC and aids in testing new targeted drugs.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- Intratumoral heterogeneity is a key factor in breast cancer drug resistance.
- This heterogeneity is influenced by oncogenic drivers and tumor precursor cells.
- Understanding and modeling this heterogeneity is crucial for developing effective therapies.
Purpose of the Study:
- To engineer a mouse mammary tumor model with defined genetic perturbations to create intratumoral heterogeneity.
- To establish a preclinical model that accurately reflects the complexity of human triple-negative breast cancer (TNBC).
Main Methods:
- Utilized Ink4a/Arf knockout mice, susceptible to tumors.
- Introduced HRAS(G12V) oncogene into Ink4a/Arf(-/-) mammary cells in vitro.
- Inoculated engineered cells into syngeneic mice mammary fat pads to induce tumors.
Main Results:
- Achieved 100% tumorigenesis with tumors resembling human TNBC (ER-, PR-, HER2-).
- Observed significant intratumoral heterogeneity with two subpopulations: CD49f(-) quiescent cells and CD49f(+) cells.
- Found that CD49f(-) quiescent cells exhibited higher tumor-initiating potential and overexpressed epithelial-to-mesenchymal transition genes.
Conclusions:
- The engineered mouse model successfully recapitulates intratumoral heterogeneity found in human TNBC.
- This model provides a valuable platform for evaluating novel molecular targeted drugs against TNBC.
- The findings highlight the role of specific cell subpopulations and EMT pathways in TNBC progression.
Related Concept Videos
02:43Mouse Models of Cancer Study
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
02:23Abnormal Proliferation