Cell type of origin as well as genetic alterations contribute to breast cancer phenotypes
Metrics: PDF 1885 views | HTML 2204 views | ?
Divya Bhagirath1,*, Xiangshan Zhao1,*, William W. West2,7, Fang Qiu3, Hamid Band1,2,4,5,6,7, Vimla Band1,7
1Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, 985805 Nebraska Medical Center, Omaha, NE 68198
2Departments of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE 68198
3Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, 984375 Nebraska Medical Center, Omaha, NE 68198
4Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198
5Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, 985800 Nebraska Medical Center, Omaha, NE 68198
6Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE 68198
7Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE 68198
* These authors have contributed equally to this work
Vimla Band, e-mail: [email protected]
Keywords: Transformation, stem cells, xenograft, breast cancer, metastasis
Received: November 02, 2014 Accepted: April 10, 2015 Published: April 22, 2015
Breast cancer is classified into different subtypes that are associated with different patient survival outcomes, underscoring the importance of understanding the role of precursor cell and genetic alterations in determining tumor subtypes. In this study, we evaluated the oncogenic phenotype of two distinct mammary stem/progenitor cell types designated as K5+/K19− or K5+/K19+ upon introduction of identical combinations of oncogenes-mutant H-Ras (mRas) and mutant p53 (mp53), together with either wild-type ErbB2(wtErbB2) or wild-type EGFR (wtEGFR). We examined their tumor forming and metastasis potential, using both in-vitro and in-vivo assays. Both the combinations efficiently transformed K5+/K19− or K5+/K19+ cells. Xenograft tumors formed by these cells were histologically heterogeneous, with variable proportions of luminal, basal-like and claudin-low type components depending on the cell types and oncogene combinations. Notably, K5+/K19− cells transformed with mRas/mp53/wtEGFR combination had a significantly longer latency for primary tumor development than other cell lines but more lung metastasis incidence than same cells expressing mRas/mp53/wtErbB2. K5+/K19+ cells exhibit shorter overall tumor latency, and high metastatic potential than K5+/K19− cells, suggesting that these K19+ progenitors are more susceptible to oncogenesis and metastasis. Our results suggest that both genetic alterations and cell type of origin contribute to oncogenic phenotype of breast tumors.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.