Project description:Mammary alveologenesis is abrogated in the absence of the transcription factors STAT5A/5B that mediate cytokine signaling. To reveal the underlying causes for this developmental block we studied mammary stem and progenitor cells. While loss of STAT5A/5B did not affect the stem cell population and their ability to form mammary ducts, luminal progenitors were greatly reduced and unable to form alveoli during pregnancy. Temporally-controlled expression of transgenic STAT5A in mammary epithelium lacking STAT5A/5B restored the luminal progenitor population and rescued alveologenesis in a reversible fashion in vivo. Taken together, STAT5A is necessary and sufficient for the establishment of luminal progenitor cells. The mammary tissues from two mice of each genotype were collected 6 days (sample 9 and 11 were WT)
Project description:Mammary alveologenesis is abrogated in the absence of the transcription factors STAT5A/5B that mediate cytokine signaling. To reveal the underlying causes for this developmental block we studied mammary stem and progenitor cells. While loss of STAT5A/5B did not affect the stem cell population and their ability to form mammary ducts, luminal progenitors were greatly reduced and unable to form alveoli during pregnancy. Temporally-controlled expression of transgenic STAT5A in mammary epithelium lacking STAT5A/5B restored the luminal progenitor population and rescued alveologenesis in a reversible fashion in vivo. Taken together, STAT5A is necessary and sufficient for the establishment of luminal progenitor cells.
Project description:Highly purified subpopulations of primitive bipotent and committed luminal progenitor cells as well as mature luminal and myoepithelial cells from normal human mammary tissue were isolated and compared their transcriptomes obtained using the Affymetrix GeneChip Human X3P Array. Experiment Overall Design: 12 Afffymetrix array hybridizations were performed on RNA samples extracted from highly purified subpopulations of primitive bipotent and committed luminal progenitor cells as well as mature luminal and myoepithelial cells isolate from 3 different normal human mammary tissue.
Project description:The goal of this study was to determine the genes regulated by ID4 in mammary epithelial subpopulations. Basal, luminal progenitor, and mature luminal mammary epithelial subpopulations were FACS-sorted from adult mice that were either WT or ID4 KO in quadruplicate. RNA-seq and differential gene expression analysis was performed.
Project description:Female patients with multiple endocrine neoplasia type 1 are at increased risk to develop breast cancer. We analyzed gene expression after silencing of the MEN1 gene in primary human mammary luminal progenitor cells to identify menin target genes involved in mammary tumorigenesis.
Project description:We used a mouse strain in which one Tbx3 gene was replaced with the yellow fluorescent protein variant Venus. Luminal cells had either very high Tbx3 promoter activity or not at all. We performed an expression analysis on luminal mammary epithelial cells sorted based on their Venus expression (reporting Tbx3 promoter activity) to investigate the difference between these two cell populations. Mammary epithelial cells from 3 Tbx3-Venus-KI adult virgin female mice (FVB background) were pooled and luminal cells were sorted into a Venus-hi and a Venus-neg sample. There were no repeats for this study.
Project description:Mammary stem and progenitor cells are essential for mammary gland homeostasis and are also candidates for cells of origin of mammary tumors. Here, we provide evidence that the protein kinase p38a is required for the differentiation of luminal progenitor cells through modulation of the transcription factors Runx1 and Foxa1. Moreover, using a mouse model for breast cancer initiated by luminal cells, we show that p38a downregulation in mammary epithelial cells reduces tumorigenesis, which correlates with reduced numbers of tumor-initiating cells. Our results identify p38a as a key regulator of luminal progenitor cell fate that facilitates mammary tumor formation.
Project description:Claudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS as well as regulators of EMT play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.
Project description:The retinoblastoma tumor suppressor, Rb, is implicated in luminal-B and basal-like breast carcinomas, yet its effect on mammary gland development and causal role in breast cancer subtypes remain undefined. Here we show that conditional deletion of Rb in mouse mammary epithelium led to expansion of the stem/progenitor cells and to focal acinar hyperplasia with squamous metaplasia. These uniform lesions progressed into histologically diverse, transplantable mammary adenocarcinomas and adenosquamous carcinomas with features of luminal-B or basal-like carcinomas. A subset of basal-like but none of the luminal-B tumors expressed mutant p53. These results demonstrate a causative role for Rb in the etiology of breast cancer subtypes and implicate p53 status as a determinant of tumor phenotype after Rb loss. Keywords: reference x sample Will be updated soon