Glucan from Oudemansiella raphanipes suppresses breast cancer proliferation and metastasis by regulating macrophage polarization and the WNT/ß-catenin signaling pathway.

Background: The glucan extract of Oudemansiella raphanipes (Orp) has multiple biological properties, similar to extracts of other natural edible fungi. Drugs traditionally used in cancer treatment are associated with several drawbacks, such as side effects, induction of resistance, and poor prognosis, and many recent studies have focused on polysaccharides extracted from natural sources as alternatives. Our study focuses on the therapeutic role and molecular mechanism of action of Orp in breast cancer progression. Methods: MMTV-PyMT transgenic mice were used as the spontaneous breast cancer mice model. Immunoblotting, hematoxylin-eosin staining, immunohistochemistry, and immunofluorescence were used to evaluate the tumor behaviors in breast cancer. The inflammatory cell model was constructed using TNF-α. Macrophage activation and WNT/ß-catenin signaling were assayed using western blotting and immunofluorescence. Results: Orp management significantly inhibited tumor growth and promoted tumor cell apoptosis in MMTV-PyMT transgenic mice. Besides, the Orp challenge also attenuated the ability of breast tumors to metastasize into lung tissues. Mechanistically, Orp treatment restrained the polarization of M1 macrophages to M2 macrophages and suppressed WNT/ß-catenin signaling in mouse tumor tissues, which implied that Orp-mediated tumor inhibition partly occurred via regulating the inflammatory response. Findings from in vitro experiments confirmed that Orp inhibited the TNF-α-induced nuclear transportation of ß-catenin, thus preventing inflammation signaling and the expression of c-Myc in MCF-7 cells. Conclusion: Orp inhibits breast cancer growth and metastasis by regulating macrophage polarization and the WNT/ß-catenin signaling axis. The findings of this study suggest that Orp may be a promising therapeutic strategy for breast cancer.

Identification and validation of molecular subtypes and a 9-gene risk model for breast cancer.

The long-term efficacy of treatment, heterogeneity, and complexity in the tumor microenvironment remained a clinical challenge in breast cancer (BRCA). There is a need to classify and refine appropriate therapeutic intervention decisions. A stable subtype classification based on gene expression associated with neoadjuvant chemotherapy (NAC) prognosis and assessment on the clinical features, immune infiltration, and mutational characteristics of the different subcategories was performed using ConsensusClusterPlus. We constructed a prognostic model by the least absolute shrinkage and selection operator regression (LASSO) and univariate Cox regression method and further investigated the association between the risk model and clinical features, mutation and immune characteristics of BRCA. We constructed 3 molecular clusters associated with NAC. We found that cluster 1 had the best prognosis, while cluster 3 showed a poor prognosis. Cluster 3 were associated with the advance stage, higher mutation score, activated oncogenic, and lower tumor immune dysfunction and exclusion (TIDE) score. Subsequently, we constructed a prognosis-related risk model comprising 9 genes (RLN2, MSLN, SAPCD2, LY6D, CACNG4, TUBA3E, LAMP3, GNMT, KLHDC7B). The higher-risk group exhibited lower immune infiltration and demonstrated improved overall survival (OS) in both the independent validation cohort. Finally, by combining clinicopathological features with the NAC-related prognostic risk model, we enhanced the accuracy of survival prediction and model performance. Here, we revealed 3 new molecular subtypes based on prognosis-related genes for BRCA NAC and developed a prognostic risk model. It has the potential to aid in the selection of appropriate individualized treatment and the prediction of patient prognosis.

ß-Glucan produced by Lentinus edodes suppresses breast cancer progression via the inhibition of macrophage M2 polarization by integrating autophagy and inflammatory signals.

BACKGROUND: ß-Glucan from Lentinus edodes (LNT), an edible mushroom, possesses strong anticancer activity. However, the therapeutic effects of LNT during the occurrence and progression of breast cancer and their underlying molecular mechanisms have not been elucidated. METHODS: Mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) transgenic mice were used as a breast cancer mouse model. Hematoxylin and eosin, immunohistochemical, and immunofluorescence staining were performed for histopathological analysis. Moreover, we developed an inflammatory cell model using tumor necrosis factor-α (TNF-α). Macrophage polarization was assessed using western blot analysis and immunofluorescence. RESULTS: Orphan nuclear receptor 77 (Nur77) and sequestosome-1 (p62) were highly expressed and positively correlated with each other in breast cancer tissues. LNT significantly inhibited tumor growth, ameliorated inflammatory cell infiltration, and induced tumor cell apoptosis in PyMT transgenic mice. Moreover, LNT attenuated the ability of tumors to metastasize to lung tissue. Mechanistically, LNT treatment restrained macrophage polarization from M1 to M2 phenotype and promoted autophagic cell death by inhibiting Nur77 expression, AKT/mTOR signaling, and inflammatory signals in breast tumor cells. However, LNT did not exhibit a direct pro-autophagic effect on tumor cell death, except for its inhibitory effect on Nur77 expression. LNT-mediated autophagic tumor cell death depends on M1 macrophage polarization. In in vitro experiments, LNT inhibited the upregulation of p62, autophagy activation, and inflammatory signaling pathways in Nur77 cells. CONCLUSION: LNT inhibited macrophage M2 polarization and subsequently blocked the AKT/mTOR and inflammatory signaling axes in breast cancer cells, thereby promoting autophagic tumor cell death. Thus, LNT may be a promising therapeutic strategy for breast cancer.