Sfrp3 modulates stromal–epithelial crosstalk during mammary gland development by regulating Wnt levels

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.

Comprehensive Analysis of the Expression and Prognosis for SFRPs in Breast Carcinoma

“…SFRP3 contains a CRD that regulates Wnt signaling. Bernascone et al 25 found that loss of SFRP3 predisposed mice to Figure 4. The expression of SFRPs across different cancer stages.…”

“…SFRP3 contains a CRD that regulates Wnt signaling. Bernascone et al 25 found that loss of SFRP3 predisposed mice to invasive BC. Schlensog et al 26 also reported a tumor-suppressive role of SFRP3 in lung adenocarcinoma likely via the regulation of canonical Wnt signaling.…”

“…SFRP3 contains a CRD that regulates Wnt signaling. Bernascone et al 25 found that loss of SFRP3 predisposed mice to We used log2(TPM þ 1) for y-axis log-scale, the method for differential gene expression analysis is one-way analysis of variance, using pathological stage as variable for calculating differential expression. The larger F, the better the study fit, and P-value <0.05 as statistically significant (GEPIA Database).…”

The risk variant rs11836367 contributes to breast cancer onset and metastasis by attenuating Wnt signaling via regulatingNTN4expression

“…Co-immunoprecipitation of NTN4 protein with different Wnt ligands was conducted as previously described with modification ( 60 ). Briefly, 293T cells were plated into 100-mm plates on the day before transfection.…”

“…The glutathione S -transferase (GST) pull-down assay was performed as previously reported ( 60 , 61 ). NTN4 △SP , NTN4 LN , NTN4 LE , and NTN4 NTR sequences were cloned into the pGEX-6P-1 plasmid using the ClonExpress II One Step Cloning Kit (Vazyme, Nanjing, China) according to the manufacturer’s instructions.…”