Abstract
Mammary stroma is essential for epithelial morphogenesis and development. Indeed, postnatal mammary gland (MG) development is controlled locally by the repetitive and bi-directional cross-talk between the epithelial and the stromal compartment. However, the signalling pathways involved in stromal–epithelial communication are not entirely understood. Here, we identify Sfrp3 as a mediator of the stromal–epithelial communication that is required for normal mouse MG development. Using Drosophila wing imaginal disc, we demonstrate that Sfrp3 functions as an extracellular transporter of Wnts that facilitates their diffusion, and thus, their levels in the boundaries of different compartments. Indeed, loss of Sfrp3 in mice leads to an increase of ductal invasion and branching mirroring an early pregnancy state. Finally, we observe that loss of Sfrp3 predisposes for invasive breast cancer. Altogether, our study shows that Sfrp3 controls MG morphogenesis by modulating the stromal-epithelial cross-talk during pubertal development.
Highlights
Mammary stroma is essential for epithelial morphogenesis and development
We demonstrate that SFRP3 functions as an extracellular transporter of Wnts using the larval model of Drosophila, and show that SFRP3 control the levels of Wnts that accumulate in the stromal–epithelial boundary, modulating the proliferative and branching response of the epithelium during
We examined the expression of all secreted frizzled-related protein (Sfrp) family members during mammary gland (MG) development
Summary
Stromal and epithelial cells of the MG express Sfrp[3]. In order to investigate the role of Sfrp[3] in MG morphogenesis, we examined the expression of Sfrp[3] during MG development. We found that Wnt[2] protein accumulated at the stromal–epithelial boundary in Sfrp3−/− (Fig. 6d), while deepithelialised cleared fat pads of adult animals presented reduced levels of expression of Wnt[2] (Fig. 6e), which is consistent with the decrease we observed in pregnant mice for Wnt[2] (Supplementary Fig. 6) This data suggests that Sfrp[3] function might be related to control the accumulation of Wnt[2] at the stromal–epithelial boundary since the loss of stromal Sfrp[3] leads to an accumulation of Wnt[2] in the boundary, which is consistent with the role found for Sfrp[3] in Drosophila before. These results support the alterations in MG morphogenesis we observed in Sfrp3−/− virgin females, and reveal Sfrp[3] as a potential marker for BC susceptibility
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