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    Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium

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    Author
    Tarulli, GA; De Silva, D; Ho, V; Kunasegaran, K; Ghosh, K; Tan, BC; Bulavin, DV; Pietersen, AM
    Date
    2013-01-01
    Source Title
    Breast Cancer Research
    Publisher
    BMC
    University of Melbourne Author/s
    Tarulli, Gerard
    Affiliation
    School of BioSciences
    Metadata
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    Document Type
    Journal Article
    Citations
    Tarulli, G. A., De Silva, D., Ho, V., Kunasegaran, K., Ghosh, K., Tan, B. C., Bulavin, D. V. & Pietersen, A. M. (2013). Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium. BREAST CANCER RESEARCH, 15 (1), https://doi.org/10.1186/bcr3381.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/256108
    DOI
    10.1186/bcr3381
    Abstract
    INTRODUCTION: The molecular circuitry of different cell types dictates their normal function as well as their response to oncogene activation. For instance, mice lacking the Wip1 phosphatase (also known as PPM1D; protein phosphatase magnesium-dependent 1D) have a delay in HER2/neu (human epidermal growth factor 2), but not Wnt1-induced mammary tumor formation. This suggests a cell type-specific reliance on Wip1 for tumorigenesis, because alveolar progenitor cells are the likely target for transformation in the MMTV(mouse mammary tumor virus)-neu but not MMTV-wnt1 breast cancer model. METHODS: In this study, we used the Wip1-knockout mouse to identify the cell types that are dependent on Wip1 expression and therefore may be involved in the early stages of HER2/neu-induced tumorigenesis. RESULTS: We found that alveolar development during pregnancy was reduced in Wip1-knockout mice; however, this was not attributable to changes in alveolar cells themselves. Unexpectedly, Wip1 allows steroid hormone-receptor-positive cells but not alveolar progenitors to activate STAT5 (signal transducer and activator of transcription 5) in the virgin state. In the absence of Wip1, hormone-receptor-positive cells have significantly reduced transcription of RANKL (receptor activator of nuclear factor kappa-B ligand) and IGF2 (insulin-like growth factor 2), paracrine stimulators of alveolar development. In the MMTV-neu model, HER2/neu activates STAT5 in alveolar progenitor cells independent of Wip1, but HER2/neu does not override the defect in STAT5 activation in Wip1-deficient hormone-sensing cells, and paracrine stimulation remains attenuated. Moreover, ERK (extracellular signal-regulated kinase) activation by HER2/neu in hormone-sensing cells is also Wip1 dependent. CONCLUSIONS: We identified Wip1 as a potentiator of prolactin and HER2/neu signaling strictly in the molecular context of hormone-sensing cells. Furthermore, our findings highlight that hormone-sensing cells convert not only estrogen and progesterone but also prolactin signals into paracrine instructions for mammary gland development. The instructive role of hormone-sensing cells in premalignant development suggests targeting Wip1 or prolactin signaling as an orthogonal strategy for inhibiting breast cancer development or relapse.

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