Characterization of mammary cancer stem cells in the MMTV-PyMT mouse model.
Ma Jun,Lanza Denise Grant,Guest Ian,Uk-Lim Chang,Glinskii Anna,Glinsky Gennadi,Sell Stewart
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
Breast cancer stem cells, the root of tumor growth, present challenges to investigate: Primary human breast cancer cells are difficult to establish in culture and inconsistently yield tumors after transplantation into immune-deficient recipient mice. Furthermore, there is limited characterization of mammary cancer stem cells in mice, the ideal model for the study of breast cancer. We herein describe a pre-clinical breast cancer stem cell model, based on the properties of cancer stem cells, derived from transgenic MMTV-PyMT mice. Using a defined set of cell surface markers to identify cancer stem cells by flow cytometry, at least four cell populations were recovered from primary mammary cancers. Only two of the four populations, one epithelial and one mesenchymal, were able to survive and proliferate in vitro. The epithelial population exhibited tumor initiation potential with as few as 10 cells injected into syngeneic immune-competent recipients. Tumors initiated from injected cell lines recapitulated the morphological and physiological components of the primary tumor. To highlight the stemness potential of the putative cancer stem cells, B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) expression was knocked down via shRNA targeting Bmi-1. Without Bmi-1 expression, putative cancer stem cells could no longer initiate tumors, but tumor initiation was rescued with the introduction of a Bmi-1 overexpression vector in the Bmi-1 knockdown cells. In conclusion, our data show that primary mammary cancers from MMTV-PyMT mice contain putative cancer stem cells that survive in culture and can be used to create a model for study of mammary cancer stem cells.
Mammary Tumorigenesis and Metabolome in Male Adipose Specific Monocyte Chemotactic Protein-1 Deficient MMTV-PyMT Mice Fed a High-Fat Diet.
Yan Lin,Sundaram Sneha,Rust Bret M,Picklo Matthew J,Bukowski Michael R
Frontiers in oncology
Male breast cancer, while uncommon, is a highly malignant disease. Monocyte chemotactic protein-1 (MCP-1) is an adipokine; its concentration in adipose tissue is elevated in obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose-specific knockout [designated as or wild-type (WT)] were fed the AIN93G standard diet or a high-fat diet (HFD) for 25 weeks. mice had lower adipose expression than WT mice. Adipose deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD compared to their WT counterparts. mice had a longer tumor latency (25.2 weeks 18.0 weeks) and lower tumor incidence (19% 56%), tumor progression (2317% 4792%), and tumor weight (0.23 g 0.64 g) than WT mice. Plasma metabolomics analysis identified 56 metabolites that differed among the four dietary groups, including 22 differed between and WT mice. Pathway and network analyses along with discriminant analysis showed that pathways of amino acid and carbohydrate metabolisms are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis in male MMTV-PyMT. The potential involvement of adipose-derived MCP-1 in metabolomics warrants further investigation on its role in causal relationships between cancer metabolism and mammary tumorigenesis in this male MMTV-PyMT model.