Estrogen receptor α (ERα) is a nuclear receptor that functions as a ligand-activated transcription factor. Besides its genomic action in nuclei, ERα could exert nongenomic actions at the plasma membrane. To investigate the mechanism underlying the nongenomic action of ERα in breast cancer cells, we generated a construct of membrane-targeted ERα (memER), an expression vector of ERα without the nuclear localizing signal and including instead the membrane-targeting sequence of Src kinase. MemER was stably expressed in human breast cancer MCF-7 cells. Cell migration test and tumorigenic assay in nude mice revealed that the in vitro motility and the in vivo proliferation activity of MCF-7 cells expressing memER were significantly enhanced compared with those of vector-transfected cells. Interestingly, the acetylation level of tubulin in memER-overexpressing cells was lower than that in control cells. We found that histone deacetylase (HDAC) 6 translocated to the plasma membrane shortly after estrogen stimulation, and rapid tubulin deacetylation subsequently occurred. We also showed that memER associated with HDAC6 in a ligand-dependent manner. Although tamoxifen is known for its antagonistic role in the ERα genomic action in MCF-7 cells, the agent showed an agonistic function in the memER-HDAC6 association and tubulin deacetylation. These findings suggest that ERα ligand dependently forms a complex with HDAC6 and tubulin at the plasma membrane. Estrogen-dependent tubulin deacetylation could provide new evidence for the nongenomic action of estrogen, which potentially contributes to the aggressiveness of ERα-positive breast cancer cells. [Cancer Res 2009;69(7):2935–40]

Background: After the outbreak of the coronavirus disease 2019 (COVID‐19), “pandemic‐associated‐frailty” or profound health deterioration, in older adults has been considered a health concern. In this study, we sought to demonstrate whether pandemic‐associated‐frailty is occurring in Japan, where the population is aging, by showing the prevalence of frailty before and during the COVID‐19 outbreak, using the same method. Methods: A total of 5222 older adults in Otawara City, Tochigi Prefecture, aged 70 and 75 were surveyed annually using a complete survey, excluding those who were certified as requiring long‐term care. Frailty during 2017–2019 before the COVID‐19 outbreak and during 2020–2021 during the COVID‐19 outbreak was determined using the Kihon Checklist (KCL). Statistical analysis was performed using the χ ² test to compare annual frailty status and Kruskal–Wallis test to compare the scores. Results: The frailty statuses over the five‐year period showed a significant decrease in Robust and a significant increase in Pre‐frailty and Frailty ( p < 0.001). Frailty increased markedly during the second year of the pandemic. Based on the category, the scores deteriorated significantly for activities of daily living ( p < 0.001), physical function ( p = 0.003), oral function ( p < 0.001), outdoor activity ( p < 0.001), and depression ( p < 0.001). Moreover, there was a significant deterioration in the total score for 25 items ( p < 0.001). In addition, a significant deterioration was observed in the total score of 23 items, excluding the social withdrawal affected by self‐restraint life ( p < 0.001). Conclusions: The population prevalence of frailty in older adults increased steadily from the pre‐pandemic year through the first and second years of the pandemic. Based on the 25 questions of the KCL, two aspects including visiting friends and going out less stood out. This suggests that pandemic‐associated‐frailty occurred in Japan.

Background: Oral health is a key factor of overall health and closely associated with well-being and quality of life. Mastication is one the most important oral functions and may deteriorate with aging. Evidence on association between masticatory dysfunction and frailty in the literature is scarce and not coherent. Methods: A search strategy was developed to conduct a systematic review of the literature in PubMed, CINAHL, and AMED in accordance with the PRISMA 2020 guidelines. We searched for studies published in 2000 or later that examined associations between self-reported masticatory dysfunction and frailty risk. The reference lists of the relevant articles were reviewed for additional studies. We calculated pooled odds ratios (OR) of association between self-reported masticatory dysfunction and the risk of frailty by fixed-effects meta-analysis. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess risk of bias. Publication bias was assessed by visually inspecting a funnel plot. Results: A total of 285 studies were identified by the literature search. Among 5 studies selected for this review, 4 cross-sectional studies including a total of 7425 individuals were used for meta-analysis. The pooled results by a fixed-effects model showed that there was a significant association between self-reported masticatory dysfunction and frailty risk (pooled OR = 1.83, 95%CI = 1.55–2.18, p<0.00001). There was no evidence of publication bias observed. Conclusions: This systematic review and meta-analysis highlighted pooled cross-sectional evidence that community-dwelling older people who report masticatory dysfunction are significantly more likely to be frail than those who do not. The limitations of this study are: inclusion of only cross-sectional studies, no gold standard to measure masticatory functions, self-reported information on masticatory function, and the limited number of included studies. More longitudinal studies are warranted for further understanding of the causal pathways and elucidate underlying mechanisms. Registration: PROSPERO CRD42021277173

Durability of androgen-deprivation therapy (ADT) for prostate cancer (PC) is limited. Additional selective estrogen receptor modulators (SERMs) may prolong the durability of ADT, because androgen and estrogen signaling drive PC progression. Men with treatment-naïve bone metastatic PC were randomly assigned in 1:1:1 fashion to receive ADT, toremifene 60 mg plus ADT (TOPADT), or raloxifene 60 mg plus ADT (RAPADT). The primary endpoint was the biochemical recurrence (BCR) rate, and secondary endpoints were changes of scores of the visual analogue scale (VAS) and the functional assessment of cancer therapy (FACT). A total of 15 men, 5 each, were allocated to one of the three treatment arms. The basal serum prostate-specific antigen (PSA) level was 198 ng/mL (median, range; 30–8428). Bone metastases were graded as 1 (n = 11), 2 (n = 3), and 3 (n = 1) by the extent of disease. During the median follow-up period of 1370 days (range; 431–1983), BCR occurred in 3, 0 and 2 men in ADT, TOPADT and RAPADT group, respectively. The 5-year BCR-free rate was 30, 100 and 53 %, in ADT, TOPADT and RAPADT group, respectively (p = 0.04, ADT v.s. TOPADT, p = 0.48, ADT v.s. RAPADT and p = 0.12, TOPADT v.s. RAPADT). Scores of VAS improved in all groups and remained stable throughout the study. This analysis is limited as a preliminary result in a single center. Toremifene with conventional ADT significantly improved the BCR rate in treatment-naïve bone metastatic PC. Further clinical trials are warranted to confirm the promising clinical efficacy of this combination therapy. The protocol was registered at the University Hospital Medical Information Network ( UMIN ID;0,000,064,000 ) in Sep 25, 2011.