The Wnt family of secreted proteins are involved in mammary gland development and tumorigenesis. It has recently been shown that Wnt ligands promote M2 macrophage polarization and so we sought to determine the effects of a Wnt signaling antagonist, Secreted Frizzled Related Protein 1 (SFRP1), on M2 marker expression. We measured a murine M2 marker (Arg1) in mice with a targeted deletion of Sfrp1 during different stages of mammary gland development including puberty, pregnancy, and lactation, as well as in response to obesity. Next, to determine whether Wnt signaling/antagonism affects human M2 markers (CD209 and CCL18), we treated a human patient derived explant (PDE) breast tissue sample with exogenous Wnt3a in the presence and absence of rSFRP1. Finally, we expanded our PDE study to 13 patients and performed bulk RNAseq analysis following the treatment described above. We found that in loss of Sfrp1 in the murine mammary gland increased Arg1 expression. Moreover, we showed that Wnt3a increases CD209 and CCL18 mRNA and protein expression in breast PDEs and that their expression is decreased in response to rSFRP1. Our RNAseq analysis unveiled novel genes that were affected by Wnt3a treatment and subsequently reversed when rSFRP1 was added. Validation of these data exhibited that chemokines involved in promoting macrophage polarization and cancer metastasis, including CCL11 and CCL26, were stimulated by Wnt3a signaling and their expression was abrogated by treatment with rSFRP1. Our data suggest that SFRP1 may be an important mediator that tempers Wnt signaling in the tumor microenvironment.

Wnt 分泌蛋白家族参与乳腺发育和肿瘤发生。最近表明，Wnt 配体促进 M2 巨噬细胞极化，因此我们试图确定 Wnt 信号传导拮抗剂、分泌型卷曲相关蛋白 1 (SFRP1) 对 M2 标记物表达的影响。我们在乳腺发育的不同阶段（包括青春期、妊娠和哺乳期）以及对肥胖的反应中，测量了靶向删除Sfrp 1 的小鼠的鼠 M2 标记物 ( Arg1 )。接下来，为了确定 Wnt 信号传导/拮抗是否影响人类 M2 标记物（CD209和CCL18），我们在存在和不存在 rSFRP1 的情况下用外源 Wnt3a 处理人类患者外植体 (PDE) 乳腺组织样本。最后，我们将 PDE 研究扩展到 13 名患者，并在上述治疗后进行了批量 RNAseq 分析。我们发现，小鼠乳腺中Sfrp 1缺失后，Arg 1 表达增加。此外，我们发现 Wnt3a 增加乳腺 PDE 中CD209和CCL18 mRNA 和蛋白的表达，并且它们的表达响应 rSFRP1 而降低。我们的 RNAseq 分析揭示了受 Wnt3a 处理影响并随后在添加 rSFRP1 时逆转的新基因。这些数据的验证表明，参与促进巨噬细胞极化和癌症转移的趋化因子（包括CCL11和CCL26）受到 Wnt3a 信号传导的刺激，并且通过 rSFRP1 治疗消除了它们的表达。我们的数据表明，SFRP1 可能是调节肿瘤微环境中 Wnt 信号传导的重要介质。