Oncotarget

Research Papers:

Cell type of origin as well as genetic alterations contribute to breast cancer phenotypes

Divya Bhagirath, Xiangshan Zhao, William W. West, Fang Qiu, Hamid Band and Vimla Band _

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Oncotarget. 2015; 6:9018-9030. https://doi.org/10.18632/oncotarget.3379

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Abstract

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

Correspondence to:

Vimla Band, e-mail: vband@unmc.edu

Keywords: Transformation, stem cells, xenograft, breast cancer, metastasis

Received: November 02, 2014     Accepted: April 10, 2015     Published: April 22, 2015

ABSTRACT

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.


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