Cell type of origin as well as genetic alterations contribute to breast cancer phenotypes.
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.
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Divya
D
Bhagirath
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Xiangshan
X
Zhao
Departments of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
William W
WW
West
Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Fang
F
Qiu
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Hamid
H
Band
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Vimla
V
Band
D000818:Animals; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics / Q000473:pathology; D002277:Carcinoma / Q000235:genetics / Q000473:pathology / Q000556:secondary; D002461:Cell Line, Transformed; D019070:Cell Lineage; D000066673:Cell Self Renewal; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004847:Epithelial Cells / Q000737:chemistry / Q000473:pathology; D005260:Female; D052138:Genes, Neoplasm; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D016158:Genes, p53; D011905:Genes, ras; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D019098:Telomerase / Q000235:genetics; D014161:Transduction, Genetic; D019076:Transgenes; D014410:Tumor Stem Cell Assay
D019098:Telomerase
breast cancer; metastasis; stem cells; transformation; xenograft