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

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dc.contributor.authorTarulli, G.
dc.contributor.authorDe Silva, D.
dc.contributor.authorHo, V.
dc.contributor.authorKunasegaran, K.
dc.contributor.authorGhosh, K.
dc.contributor.authorTan, B.
dc.contributor.authorBulavin, D.
dc.contributor.authorPietersen, A.
dc.date.issued2013
dc.description.abstractINTRODUCTION: 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.
dc.description.statementofresponsibilityGerard A Tarulli, Duvini De Silva, Victor Ho, Kamini Kunasegaran, Kakaly Ghosh, Bryan C Tan, Dmitry V Bulavin, and Alexandra M Pietersen
dc.identifier.citationBreast Cancer Research, 2013; 15(1):R10-1-R10-17
dc.identifier.doi10.1186/bcr3381
dc.identifier.issn1465-5411
dc.identifier.issn1465-542X
dc.identifier.urihttp://hdl.handle.net/2440/95509
dc.language.isoen
dc.publisherBiomed Central
dc.rights© 2013 Tarulli et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.source.urihttps://doi.org/10.1186/bcr3381
dc.subjectCell Transformation, Neoplastic
dc.titleHormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium
dc.typeJournal article
pubs.publication-statusPublished

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