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 tumour formation. This suggests a cell type-specific reliance on Wip1 for tumourigenesis since alveolar progenitor cells are the likely target for transformation in the MMTV(mouse mammary tumour virus)-neu but not MMTV-wnt1 breast cancer model.

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.