Search

Breast cancer subtypes display different metastatic organotropism. Identification of the mechanisms underlying subtype-specific organotropism could help uncover potential approaches to prevent and treat metastasis. In this study, we found that forkhead box F2 (FOXF2) promoted the seeding and proliferative recovery from dormancy of luminal breast cancer (LumBC) and basal-like breast cancer (BLBC) cells in the bone by activating the NF-κB and BMP signaling pathways. FOXF2 promoted LumBC cell seeding but not proliferative recovery in the lung by activating the BMP signaling pathway. Conversely, FOXF2 suppressed the seeding and proliferative recovery of BLBC cells in the lung by repressing the TGFβ signaling pathway. FOXF2 directly upregulated RelA/p65 transcription and expression in LumBC and BLBC cells by binding to the RELA proximal promoter region and RelA/p65 bound to the FOXF2 proximal promoter region to upregulate expression, forming a positive feedback loop. Targeting the NF-κB pathway efficiently prevented the metastasis of FOXF2-overexpressing breast cancer cells to the bone, whereas inhibiting TGFβ signaling blocked the metastasis of BLBC with low FOXF2 expression to the lung. These findings uncover critical mechanisms of breast cancer subtype-specific organotropism and provide insights into precision assessment and treatment strategies. Significance: FOXF2 regulates signaling pathways in a subtype-specific manner to coordinate the fate of disseminated breast cancer cells in distant organs, suggesting that FOXF2 functions could be harnessed to prevent organ-specific metastasis. See related commentary by Bado, p. 639., (©2024 American Association for Cancer Research.)

Background: Bisdemethoxycurcumin (BDMC), the primary active compound found in turmeric, exhibits diverse pharmacological properties. The study aimed to investigate the mechanisms underlying the protective effects of BDMC in traumatic brain injury (TBI)., Methods: A rat TBI model was established using the Feeney's freefall epidural impact method, followed by BDMC treatment. Rat cortical neuron cells were exposed to hydrogen peroxide (H 2 O 2 ) to induce oxidative stress and then treated with BDMC. The cells were also pretreated with autophagy inhibitor 3-MA and heat shock protein 90 alpha family class A member 1 (HSP90AA1) inhibitor 17-AAG. Additionally, the experiments also involved treating H 2 O 2 -exposed cortical neurons with 17-AAG and silencing HSP90AA1 expression. Co-immunoprecipitation was utilized to verify interactions between HSP90AA1 and transcription factor EB (TFEB), TFEB and nuclear factor erythroid 2 related factor 2 (Nrf2), and the localization of these complexes in the cytoplasm and nucleus., Results: BDMC treatment significantly reduced modified neurological severity scores, brain water content, inflammatory infiltration, oxidative stress, and apoptosis in the cerebral cortex of TBI rats. Additionally, BDMC treatment elevated the expression of Beclin 1 and light chain 3 (LC3) II/LC3 I ratio while decreasing p62 expression. It also promoted TFEB nuclear translocation and increased HSP90AA1 levels in both the cytoplasm and nucleus, along with elevated nuclear Nrf2 expressions in TBI models. In vitro experiments showed decreased malondialdehyde levels, elevated glutathione peroxidase and superoxide dismutase levels upon BDMC treatment, along with repressed cortical neurons apoptosis, elevated Beclin 1 and LC3 II/LC3 I expressions, decreased p62 expressions, reduced cytoplasmic TFEB expression, increased nuclear TFEB and Nrf2 expression, and elevated HSP90AA1 expression in the cytoplasm and nucleus. Mechanistically, BDMC mediated autophagy and oxidative stress by activating HSP90AA1/TFEB/Nrf2 axis. Finally, HSP90AA1 was shown to regulate Nrf2 expression by binding to TFEB in the cellular model., Conclusions: BDMC alleviated TBI in rats by regulating autophagy and oxidative stress through HSP90AA1-mediated nuclear translocation of TFEB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)