The tumor microenvironment (TME) is heterogeneous and contains a multiple cell population with surrounded immune cells, which plays a major role in regulating metastasis. The multifunctional pathways, Hedgehog (Hh), Wnt, Notch, and NF-kB, cross-regulates metastasis in breast cancer. This review presents substantial evidence for cross-regulation of TME components and signaling pathways, which makes breast TME more heterogeneous and complex, promoting breast cancer progression and metastasis as a highly aggressive form. We discoursed the importance of stromal and immune cells as well as their crosstalk in bridging the metastasis. We also discussed the role of Hh and Notch pathways in the intervention between breast cancer cells and macrophages to support TME; Notch signaling in the bidirectional communication between cancer cells and components of TME; Wnt signal pathway in controlling the factors responsible for EMT and NF-κB pathway in the regulation of genes controlling the inflammatory response. We also present the role of exosomes and their miRNAs in the cross-regulation of TME cells as well as pathways in the reprogramming of breast TME to support metastasis. Finally, we examined and discussed the targeted small molecule inhibitors and natural compounds targeting developmental pathways and proposed small molecule natural compounds as potential therapeutics of TME based on the multitargeting ability. In conclusion, the understanding of the molecular basis of the cross-regulation of TME pathways and their inhibitors helps identify molecular targets for rational drug discovery to treat breast cancers.

肿瘤微环境（TME）是异质的，包含多个细胞群，周围有免疫细胞，在调节转移中起主要作用。多功能通路 Hedgehog (Hh)、Wnt、Notch 和 NF-kB 交叉调节乳腺癌的转移。这篇综述为 TME 成分和信号通路的交叉调节提供了大量证据，这使得乳腺 TME 更加异质和复杂，促进了乳腺癌进展和转移作为一种高度侵袭性的形式。我们讨论了基质细胞和免疫细胞的重要性以及它们在桥接转移中的串扰。我们还讨论了 Hh 和 Notch 通路在干预乳腺癌细胞和巨噬细胞以支持 TME 中的作用；癌细胞与 TME 成分之间双向通信中的 Notch 信号传导；Wnt信号通路在控制EMT的因子和NF-κB通路中控制炎症反应的基因调控。我们还介绍了外泌体及其 miRNA 在 TME 细胞交叉调节中的作用，以及乳腺 TME 重编程以支持转移的途径。最后，我们检查并讨论了靶向发育途径的靶向小分子抑制剂和天然化合物，并基于多靶向能力提出了小分子天然化合物作为 TME 的潜在治疗剂。综上所述，