Breast cancer can be stratified into several distinct subtypes, with each subtype expressing differentiation proteins that are primarily associated with either luminal or basal cells of the normal mammary gland. Importantly, stratification of breast cancer into these subtypes is correlated with clinical outcome. In order to investigate the molecular and genetic pathways that give rise to breast cancer diversity, it is critical that in vitro and in vivo models more accurately embody the spectrum of this disease. We hypothesize that the diversity of breast cancer reflects the heterogeneity of normal breast epithelial cells from which tumors arise, and that several cell lineages including stem, progenitor and differentiated cells can acquire the regenerative qualities of cancer stem cells, leading to different tumor subtypes. To investigate the relationship between a tumor's cellular origin and breast cancer, we will adapt our recently developed lentiviral-mediated transduction method in order to induce oncogene expression in different mouse and human mammary lineages.
Specific Aim 1 seeks to establish whether novel mouse-modeling methodology could produce different tumor subtypes by expanding the spectrum of cell populations targeted by oncogenes in reconstituted mammary outgrowths.
Specific Aim 2 will investigate whether tumor-initiating cells derived from different tumor subtypes exhibit unique biological qualities since they retain molecular attributes associated with their cellular origin.
In Specific Aim 3 we will again employ cell-type targeting techniques in order to assess whether oncogenesis within different human breast cell populations would enable better recapitulation of cancer subtypes observed in patients. Taken together, the studies proposed in this grant application should answer several important questions about the association of cellular differentiation and breast cancer heterogeneity, in addition to establishing new methodology that may better model breast cancer diversity.

Public Health Relevance

Breast cancer is the second leading cause of cancer-related death in women, and it is critical that experimental models accurately replicate this disease to facilitate investigation into its causes, and to advance development of new therapeutics. The studies proposed in this grant application should answer several important questions about the causes and origins of breast cancer, in addition to establishing new versatile experimental systems that may better model cancer subtypes observed in patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Drobysheva, Daria; Smith, Brittni Alise; McDowell, Maria et al. (2015) Transformation of enriched mammary cell populations with polyomavirus middle T antigen influences tumor subtype and metastatic potential. Breast Cancer Res 17:132
Basham, Kaitlin J; Leonard, Christopher J; Kieffer, Collin et al. (2015) Dioxin exposure blocks lactation through a direct effect on mammary epithelial cells mediated by the aryl hydrocarbon receptor repressor. Toxicol Sci 143:36-45
Vaden, Rachel M; Gligorich, Keith M; Jana, Ranjan et al. (2014) The small molecule C-6 is selectively cytotoxic against breast cancer cells and its biological action is characterized by mitochondrial defects and endoplasmic reticulum stress. Breast Cancer Res 16:472
Basham, Kaitlin J; Bhonde, Vasudev R; Kieffer, Collin et al. (2014) Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor. Bioorg Med Chem Lett 24:2473-6
DeRose, Yoko S; Gligorich, Keith M; Wang, Guoying et al. (2013) Patient-derived models of human breast cancer: protocols for in vitro and in vivo applications in tumor biology and translational medicine. Curr Protoc Pharmacol Chapter 14:Unit14.23
Gligorich, Keith M; Vaden, Rachel M; Shelton, Dawne N et al. (2013) Development of a screen to identify selective small molecules active against patient-derived metastatic and chemoresistant breast cancer cells. Breast Cancer Res 15:R58
Basham, Kaitlin J; Kieffer, Collin; Shelton, Dawne N et al. (2013) Chemical genetic screen reveals a role for desmosomal adhesion in mammary branching morphogenesis. J Biol Chem 288:2261-70
Lum, David H; Matsen, Cindy; Welm, Alana L et al. (2012) Overview of human primary tumorgraft models: comparisons with traditional oncology preclinical models and the clinical relevance and utility of primary tumorgrafts in basic and translational oncology research. Curr Protoc Pharmacol Chapter 14:Unit 14.22
Smith, Brittni A; Welm, Alana L; Welm, Bryan E (2012) On the shoulders of giants: a historical perspective of unique experimental methods in mammary gland research. Semin Cell Dev Biol 23:583-90
Smith, Brittni A; Shelton, Dawne N; Kieffer, Collin et al. (2012) Targeting the PyMT Oncogene to Diverse Mammary Cell Populations Enhances Tumor Heterogeneity and Generates Rare Breast Cancer Subtypes. Genes Cancer 3:550-63

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