%0 Journal Article
%T Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium
%A Gerard A Tarulli
%A Duvini De Silva
%A Victor Ho
%A Kamini Kunasegaran
%A Kakaly Ghosh
%A Bryan C Tan
%A Dmitry V Bulavin
%A Alexandra M Pietersen
%J Breast Cancer Research
%D 2013
%I BioMed Central
%R 10.1186/bcr3381
%X 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 tumourigenesis.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.We have identified Wip1 as a potentiator of prolactin and HER2/neu signalling strictly in the molecular context of hormone-sensing cells. Furthermore, our findings highlight that hormone-sensing cells not only convert 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 signalling as an orthogonal strategy for inhibiting breast cancer development or relapse.
%U http://breast-cancer-research.com/content/15/1/R10/abstract