Abstract
IntroductionThe diversity of human breast cancer subtypes has led to the hypothesis that breast cancer is actually a number of different diseases arising from cells at various stages of differentiation. The elusive nature of the cell(s) of origin thus hampers approaches to eradicate the disease.MethodsClonal cell lines were isolated from primary transgenic polyomavirus middle T (PyVmT) luminal tumors. Mammary cancer stem cell (MaCSC) properties were examined by immunofluorescence, flow cytometry, differentiation assays and in vivo tumorigenesis.ResultsClonal cell lines isolated from primary PyVmT mouse mammary luminal tumors can differentiate into luminal, myoepithelial, alveolar and adipocyte lineages. Upon orthotopic injection, progeny of a single cell follow a pattern of progression from ductal carcinoma in situ, to adenoma, adenocarcinoma and epithelial metastasis that recapitulates the transgenic model. Tumors can evolve in vivo from hormone receptor-positive to hormone receptor-negative Her2-positive, or triple negative CD44hi basal-like and claudin-low tumors. Contrary to the current paradigm, we have defined a model in which multiple tumor subtypes can originate from a single multipotent cancer stem cell that undergoes genetic and/or epigenetic evolution during tumor progression. As in human tumors, the more aggressive tumor subtypes express nuclear p53. Tumor cell lines can also be derived from these more advanced tumor subtypes.ConclusionsSince the majority of human tumors are of the luminal subtype, understanding the cell of origin of these tumors and how they relate to other tumor subtypes will impact cancer therapy. Analysis of clonal cell lines derived from different tumor subtypes suggests a developmental hierarchy of MaCSCs, which may provide insights into the progression of human breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0615-y) contains supplementary material, which is available to authorized users.
Highlights
The diversity of human breast cancer subtypes has led to the hypothesis that breast cancer is a number of different diseases arising from cells at various stages of differentiation
To investigate whether luminal tumors harbor cancer stem cells (CSCs), multiple clonal cell lines were derived from the transgenic polyomavirus middle T (PyVmT) oncogene mouse model of luminal tumorigenesis in both the C57Bl/6 and FVB/N strains [8, 9], by culture of enzymatically digested spontaneous tumors followed by limiting dilution cloning
Luminal tumors harbor multipotent mammary cancer stem cells We first examined whether C57BL/6 Py230 and FVB/N Py9813 cells had the ability to differentiate into luminal, myoepithelial and alveolar lineages present in normal mammary glands
Summary
The diversity of human breast cancer subtypes has led to the hypothesis that breast cancer is a number of different diseases arising from cells at various stages of differentiation. Approaches to eradicate breast cancer have been hampered by the elusive nature of the cell(s) of origin that can give rise to a diverse group of tumors, some of which have the ability to metastasize. While current evidence suggests that hereditary breast cancer promoted by loss of Brca arises in luminal progenitor cells [1], the cell of origin for the majority of breast tumors, which are spontaneous in nature, remains undetermined. While putative breast cancer stem cells (CSCs) have been identified from a small subset of aggressive tumors [2], understanding whether the majority of breast cancers arise from CSCs, from clonal evolution of differentiated. We have focused this report on the C57Bl/6 Py230 cell line [10] because of its genetic stability, but similar phenotypes have been found with additional cell lines
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