Enhanced anticancer synergy of LOM612 in combination with selinexor: FOXO1 nuclear translocation-mediated inhibition of Wnt/ß-catenin signaling pathway in breast cancer.

BACKGROUND: The intricate relationship between Forkhead box O1 (FOXO1), a well-established tumor suppressor, and breast cancer (BC) remains partially elucidated. This study aims to investigate the mechanistic role of FOXO1 nuclear localization in the context of BC. METHODS: In vitro experiments employed BC cell lines MCF-7 and MDA-MB-175 treated with LOM612, a small molecule activator of FOXO nuclear-cytoplasmic shuttling, and selinexor, an exportin 1 inhibitor. Nuclear accumulation of FOXO1, its interaction with ß-catenin, and expressions of key proteins like V-Myc avian myelocytomatosis viral oncogene homolog (c-Myc), cyclin D1 and apoptosis markers were assessed. In vivo, the effects of LOM612 and selinexor were studied using MCF-7 cell-derived xenografts (CDX). RESULTS: Treatment with LOM612 exhibited a significant enhancement in nuclear accumulation of FOXO1 within BC cells. This effect coincided with suppressed migratory behavior and heightened apoptosis susceptibility in these cells. Mechanistically, LOM612 orchestrated FOXO1 to compete with transcription factors (TCF) for binding to ß-catenin in the nucleus, leading to reduced c-Myc and cyclin D1 expressions, along with elevated levels of apoptosis-related proteins. Similar trends were observed in CDX models, where LOM612 effectively suppressed tumor growth, increased FOXO1 nuclear localization, and downregulated c-Myc and cyclin D1 expressions. Importantly, selinexor synergistically reinforced the therapeutic effects of LOM612 both in vitro and in vivo. CONCLUSIONS: Collectively, this study underscores the potential of combining LOM612 and selinexor as an efficacious anti-BC strategy. The underlying mechanism involves FOXO1's nuclear translocation, which disrupts TCF-ß-catenin interactions, thus indirectly inhibiting the Wnt/ß-catenin signaling pathway.

Selinexor improves the anti-cancer effect of tucidinostat on TP53 wild-type breast cancer.

Histone deacetylase (HDAC) is closely related to the initiation and development of breast cancer (BC). Its inhibitor (HDACi) has been used to treat BC, while the efficacy of clinical trials was not reached expectations. HDACi combined with other drugs may be an effective strategy. This study explored the effect of HDACi tucidinostat combined with selinexor, an exportin 1 (XPO1) inhibitor, on ER+Her2- BC cell lines of MCF-7 (wt-TP53), MDA-MB-175 (wt-TP53), MDA-MB-134 (mut-TP53) and T47D (mut-TP53) in vitro and cell derived xenografts (CDX) of MCF-7 in nude mice in vivo. Results showed that both tucidinostat and selinexor showed better inhibitory activities on wt-TP53 BC (MCF-7 and MDA-MB-175) comparing with mut-TP53 BC (MDA-MB-134 and T47D). Tucidinostat combined with selinexor significantly improved the effects of tucidinostat alone on the proliferation and invasion inhibitions and apoptosis promotions of MCF-7 and MDA-MB-175 cells in vitro. It also significantly enhanced the effects of tucidinostat on up-regulating the expression levels of acetyl-p53, nuclear p53, total p53, p21, Bax and Cleaved Caspase-3, and down-regulating the expression levels of Cyclin D1 and Bcl-2 in MCF-7 or MDA-MB-175 cells. Results consistent with in vitro were also obtained in CDX of MCF-7 in vivo. Taken together, we believe that tucidinostat and selinexor are potentially effective drug combinations for the treatment of wt-TP53 BC, and the molecular mechanism may be through enhancing the activity of p53 in the nucleus of BC cells to suppress proliferation and invasion and promote apoptosis.

Long-term sleep habits and the risk of breast cancer among Chinese women: a case-control study.

Previous observational studies have inconsistently suggested that poor sleep is a novel risk factor for breast cancer (BC). However, these studies mainly focused on sleep duration; other sleep domains were rarely reported. The aim of this study was to evaluate the association of a broad range of sleep domains with the risk of BC incidence. We used a community-based 1 : 1 individual matched case-control design that included 401 female patients with incident BC and 401 age-matched and area-matched female controls in Jiujiang, China. Long-term sleep habits were assessed comprehensively using a validated 17-item Sleep Factors Questionnaire. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Light exposure at night (highest vs. lowest level, aOR=1.19, 95% CI: 1.06-2.68), habitual timing of sleep (after 12 a.m. midnight vs. before 22 p.m., aOR=1.12, 95% CI: 1.03-2.62), night/shift work (yes vs. no, aOR=1.38, 95% CI: 1.04-2.71), and frequency of night-time wakings (>2 per night vs. never, aOR=1.21, 95% CI: 1.10-2.96) were associated with an increased risk of BC after mutually adjusting for other sleep parameters. These positive associations remained irrespective of menopausal status and tumor estrogen receptor status. There was no association between sleep duration, sleep quality, sleep medication use, insomnia frequency, daytime nap, and the risk of BC. Our results indicate that sleep problems including light exposure at night, night/shift work, late sleeping, and frequent night waking could increase the risk of BC development, independent of other sleep factors.