Breast cancer is the second leading cause of cancer death in women. Subtypes are classified by histopathological appearance and gene expression. The basal subtype has a poor prognosis due in part to lack of therapeutic strategies. Basal tumors have unique characteristics such as high degrees of genomic instability, intra-tumor heterogeneity, and gene expression profiles similar to those of mammary stem cells. These characteristics may arise through the aberrant propagation of normal stem cells. Alternatively, mutations commonly found in this subtype may promote a stem-like state. To investigate these possibilities, pure populations of stem cells need to be characterized. Stem cell activity in the mammary gland becomes detectable in late embryonic development, peaks right before birth, diminishes rapidly after birth, and remains low in the adult. Fetal mammary stem cells (fMaSCs) are isolated by expression of the same markers as adult mammary stem cells (aMaSCs), and are similarly able to regenerate glands upon transplantation. Interestingly, gene expression profiles of populations enriched for fMaSCs, but not aMaSCs, show striking overlap with those of basal tumors. When fMaSCs were targeted with basal tumor-associated mutations and transplanted into a recipient mouse, a tumor arose within five weeks. Mice transplanted with aMaSCs bearing the same mutation have yet to develop mammary tumors after six months. These data suggest that fMaSCs are highly prone to tumorigenesis and may be a source of basal-like tumors. Lgr5 is highly expressed in fMaSCs at the peak of their activity. Lgr5+ fetal cells represent the most enriched population of fMaSCs measured in vitro. Lgr5+ cells will be analyzed throughout development to measure stem cell potential. The fate of Lgr5+ fetal and adult cells will be followed to test for the persistence of fetal-like stem cells in the adult glan. Comprehensive gene expression profiles from Lgr5+ cells will be generated throughout development to identify genes associated with a stem cell state. In the highly enriched population of Lgr5+ fMaSCs, single cell RNA sequencing will be conducted to refine these signatures. This will allow the identification of subpopulations and markers for their prospective isolation and functional analysis. The relative contributions of cell type and mutation to genomic instability and intra-tumor heterogeneity are poorly understood. The capacity of stem cells at various stages of development to give rise to basal-like tumors when targeted with mutations commonly found in this subtype will be tested. Tumors will be analyzed for genomic instability, intra-tumor heterogeneity, and gene expression. By defining the molecular correlates of a stem cell state and testing how development influences tumor phenotype, the hypothesis that fetal mammary stem cells are a source of basal tumors will be tested. This analysis will reveal links between normal development and tumor initiation and progression, providing insight into strategies for breast cancer treatment.

Public Health Relevance

By identifying molecular correlates of the stem cell state, we aim to isolate and characterize enriched populations of mammary stem cells to better understand their origin, behavior, and regulation throughout development. We will also test the capacity of fetal and adult mammary stem cells to initiate tumors when targeted with mutations commonly found in human basal breast cancer. A thorough characterization of resulting tumors will allow us to determine how developmental state of the cell of origin and mutation status dictate tumor phenotype - providing insight into strategies for the diagnosis and treatment of basal breast cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Reddy, Michael K
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Salk Institute for Biological Studies
La Jolla
United States
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