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The current mortality rates for breast cancer underscore the need for better prognostic tools; moreover, LIM and calponin homology domain 1 (LIMCH1), which is a protein with dual roles in cancer, is a promising candidate for investigation. This study employed an integrative approach combining bioinformatics analysis of The Cancer Genome Atlas (TCGA) cohort and clinical immunohistochemistry (IHC) cohort data. We analysed LIMCH1 expression patterns, its associations with clinicopathological features and prognosis, and its impact on the tumour immune microenvironment (TIME). Functional annotations and single-cell RNA sequencing (scRNA-seq) data were used to explore the underlying molecular mechanisms. Our analysis revealed that high LIMCH1 expression in breast cancer patients was significantly associated with unfavourable clinical outcomes and served as an independent prognostic indicator. The functional annotations revealed pathways related to carcinogenesis and metabolic reconfiguration, thus suggesting the role of LIMCH1 in tumour progression. Additionally, LIMCH1 expression was correlated with an immunosuppressive TIME characterized by increased numbers of M2 macrophages and reduced numbers of CD8 + T cells and NK cells. Finally, we developed a nomogram incorporating LIMCH1 expression for predicting overall survival rates, thus providing a clinically applicable tool. Our research elucidates the diverse functions of LIMCH1 in the pathogenesis of breast cancer, thus highlighting its potential utility as both a prognostic indicator and a therapeutic intervention., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical declaration and consent to participate: This article does not contain any studies with animals performed by any of the authors. The studies involving human participants were reviewed and approved by The Ethics Committee of Renmin Hospital of Wuhan University (No. WDRY2021-KS009). Written informed consent was obtained from the individual(s) for the publication of any data included in this article., (© 2025. The Author(s).)

Tamoxifen (TAM) is employed to treat premenopausal ER-positive breast cancer patients, but TAM resistance is the main reason affecting its efficacy. Thus, addressing TAM resistance is crucial for improving therapeutic outcomes. This study explored the potential role of Tinagl1, a secreted extracellular matrix protein, whose expression is compromised in TAM-resistant MCF-7 breast cancer cells (MCF-7R). We discovered that Tinagl1 plays a pivotal role in countering TAM resistance by inhibiting the EGFR and β1-integrin/focal adhesion kinase (FAK) signaling pathways, both of which are abnormally activated in MCF-7R cells and contribute to the resistance mechanism. Our data showed that the expression level of Tinagl1 in MCF-7R cells was lower compared to their wild-type counterparts, and TAM could further reduce Tinagl1 expression in MCF-7R cells, which was consistent with our microarray results. Moreover, Tinagl1 could restore the sensitivity of MCF-7R cells to TAM and inhibit the motility of MCF-7R cells by regulating epithelial-mesenchymal transition (EMT) in vitro and in vivo experiments. In addition, the level of Tinagl1 in TAM-resistant breast cancer samples was significantly lower than that in their matched primary tumors. Analysis of an online database further indicated that high Tinagl1 expression correlates with better recurrence-free survival (RFS), particularly in patients with ER-positive, HER2-negative breast cancer. Overall, this study positions Tinagl1 not only as a potential prognostic marker but also as a promising therapeutic target., (© 2025 International Union of Biochemistry and Molecular Biology.)

Breast cancer remains one of the primary causes of cancer-related death. An imbalance of oestrogen homeostasis and an inflammatory tumor microenvironment (TME) are vital risk factors for the progression and metastasis of breast cancer. Here, we showed that oestrogen homeostasis was disrupted both in breast cancer patients and in a transgenic MMTV-PyMT mouse model of breast cancer, and significant levels of hydroxylated oestrogen accumulated in the mammary tissues of these patients and mice. We also observed that tumor-associated macrophages (TAMs) were the main population of immune cells present in the breast TME. TAM-dependent tumor metastasis could be triggered by hydroxylated oestrogen via NLRP3 inflammasome activation and IL-1β production. Mechanistically, TAM-derived inflammatory cytokines induced the expression of matrix metalloproteinases (MMPs) in breast tumor cells, leading to breast tumor invasion and metastasis. Conceptually, our study reveals a previously unknown role of hydroxylated oestrogen in the reprogramming of the TME via NLRP3 inflammasome activation in TAMs, which ultimately facilitates breast cancer cells proliferation, migration, and invasion., 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 © 2024 Elsevier B.V. All rights reserved.)

Several chemotherapeutics against breast cancer are constrained by their adverse effects and chemoresistance. The development of novel chemotherapeutics to target metastatic breast cancer can bring effective clinical outcomes. Many breast cancer patients present with tumors that are positive for estrogen receptors (ERs), highlighting the importance of targeting the ER pathway in this particular subtype. Although selective estrogen receptor modulators (SERMs) are commonly used, their side effects and resistance issues necessitate the development of new ER-targeting agents. In this study, we report that a newly synthesized compound, TTP-5, a hybrid of pyrimidine, triazole, and tert-butyl-piperazine-carboxylate, effectively binds to estrogen receptor alpha (ERα) and suppresses breast cancer cell growth. We assessed the impact of TTP-5 on cell proliferation using MTT and colony formation assays and evaluated its effect on cell motility through wound healing and invasion assays. We further explored the mechanism of action of this novel compound by detecting protein expression changes using Western blotting. Molecular docking was used to confirm the interaction of TTP-5 with ERα. The results indicated that TTP-5 significantly reduced the proliferation of MCF-7 cells by blocking the ERα signaling pathway. Conversely, although it did not influence the growth of MDA-MB-231 cells, TTP-5 hindered their motility by modulating the expression of proteins associated with epithelial-mesenchymal transition (EMT), possibly via the Wnt/β-catenin pathway., (© 2024 International Union of Biochemistry and Molecular Biology.)

The primary objective of this study was to identify the factors associated with the development of depressive symptoms in elderly breast cancer (BC) patients and to construct a nomogram model for predicting these symptoms. We recruited 409 patients undergoing BC treatment in the breast departments of two tertiary-level hospitals in Jiangsu Province from November 2023 to April 2024 as our study cohort. Participants were categorized into depressed and non-depressed groups based on their clinical outcomes. Univariate and multivariate logistic regression analyses were employed to identify independent risk factors for depression among BC patients. Multivariate analysis revealed that monthly income, pain score, family support score, and physical activity score significantly influenced the onset of depression in older BC patients (P < 0.05).The risk prediction model, constructed using these identified factors, demonstrated excellent discriminatory power, as evidenced by an area under the ROC curve (AUC) of 0.824. The maximum Youden index was 0.627, with a sensitivity of 90.60%, specificity of 72.10%, and a diagnostic threshold value of 1.501. The results of the Hosmer-Lemeshow goodness-of-fit test (χ² = 3.181, P = 0.923) indicated that the model fit the data well. The calibration curve for the model closely followed the ideal curve, suggesting a strong fit and high predictive accuracy. Our nomogram model exhibited superior predictive performance, enabling healthcare professionals to identify high-risk patients early and implement preventative measures to mitigate the development of depressive symptoms. This study is a cross-sectional study that lacks longitudinal data and has a small sample size. Future research could involve larger samples, multicenter studies, and prospective designs to build better clinical predictive models., (© 2024. The Author(s).)

Rationale and Objectives: The prognosis of ductal carcinoma in situ with microinvasion (DCISM) is more similar to that of small invasive ductal carcinoma (IDC) than to pure ductal carcinoma in situ (DCIS). It is particularly important to accurately distinguish between DCISM and DCIS. The present study aims to compare the clinical and imaging characteristics of contrast-enhanced mammography (CEM) and magnetic resonance imaging (MRI) between DCISM and pure DCIS, and to identify predictive factors of microinvasive carcinoma, which may contribute to a comprehensive understanding of DCISM in clinical diagnosis and support surveillance strategies, such as surgery, radiation, and other treatment decisions., Materials and Methods: Forty-seven female patients diagnosed with DCIS were included in the study from May 2019 to August 2023. Patients were further divided into two groups based on pathological diagnosis: DCIS and DCISM. Clinical and imaging characteristics of these two groups were analyzed statistically. The independent clinical risk factors were selected using multivariate logistic regression and used to establish the logistic model [Logit(P)]. The diagnostic performance of independent predictors was assessed and compared using receiver operating characteristic (ROC) analysis and DeLong's test., Results: In CEM, the maximum cross-sectional area (CSAmax), the percentage signal difference between the enhancing lesion and background in the craniocaudal and mediolateral oblique projection (%RSCC, and %RSMLO) were found to be significantly higher for DCISM compared to DCIS (p = 0.001; p < 0.001; p = 0.008). Additionally, there were noticeable statistical differences in the patterns of enhancement morphological distribution (EMD) and internal enhancement pattern (IEP) between DCIS and DCISM (p = 0.047; p = 0.008). In MRI, only CSAmax (p = 0.012) and IEP (p = 0.020) showed significant statistical differences. The multivariate regression analysis suggested that CSAmax (in CEM or MR) and %RSCC were independent predictors of DCISM (all p < 0.05). The area under the curve (AUC) of CSAmax (CEM), %RSCC (CEM), Logit(P) (CEM), and CSAmax (MR) were 0.764, 0.795, 0.842, and 0.739, respectively. There were no significant differences in DeLong's test for these values (all p > 0.10). DCISM was significantly associated with high nuclear grade, comedo type, high axillary lymph node (ALN) metastasis, and high Ki-67 positivity compared to DCIS (all p < 0.05)., Conclusion: The tumor size (CSAmax), enhancement index (%RS), and internal enhancement pattern (IEP) were highly indicative of DCISM. DCISM tends to express more aggressive pathological features, such as high nuclear grade, comedo-type necrosis, ALN metastasis, and Ki-67 overexpression. As with MRI, CEM has the capability to help predict when DCISM is accompanying DCIS., 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 © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Aims/Background Acute radiation dermatitis is the most common complication of radiotherapy in patients with breast cancer, with mild severity relieved by symptomatic treatment and moderate-to-severe severity leading to compromised skin integrity and affecting the patient's quality of life. Therefore, this study aims to develop a prediction model for moderate-to-severe acute radiation dermatitis in patients with breast cancer to reduce its severity. Methods A retrospective analysis of 713 patients receiving radiotherapy for breast cancer at the Affiliated Cancer Hospital of Xinjiang Medical University from January 2019 to December 2023 was conducted, with January 2019 to December 2021 serving as the training group (497 patients) and January 2022 to December 2023 serving as the validation group (216 patients). Patients in the training group were classified as having mild (383 patients) or moderately severe (114 patients) acute radiation dermatitis. Binary logistic regression was used to analyze the independent effects on moderately severe acute radiation dermatitis in patients with breast cancer, and a predictive model of the bar-folding plot was constructed and validated. Results Univariable analysis revealed that age, body mass index, targeted therapy, oral tamoxifen use, hyperlipidemia, diabetes, positive regional lymph node metastasis, value-added index, and triple-negative breast cancer were factors influencing moderate-to-severe acute radiation dermatitis in patients with breast cancer. Multivariate analysis showed that body mass index, hyperlipidemia, diabetes, positive regional lymph node metastasis, and value-added index were independent influencing factors for moderate-to-severe acute radiation dermatitis in patients with breast cancer. A nomogram prediction model was constructed, and the area under the receiver operating characteristic curve of the model was 0.814 and 0.743 for internal and external validation, respectively. The calibration curve showed that the model predicted moderate-to-severe acute radiation dermatitis better, and the decision curve analysis curve showed that the model had a high clinical benefit. Conclusion This risk prediction model can predict moderate-to-severe acute radiation dermatitis in patients with breast cancer, and help clinical providers screen high-risk patients and reduce acute radiation dermatitis severity.

The mislocalization of proteins leads to breast cancer, one of the world's most prevalent cancers, which can be identified from immunohistochemical images. Here, based on the deep learning framework, location prediction models were constructed using the features of breast immunohistochemical images. Ultimately, six differentially localized proteins that with stable differentially predictive localization, maximum localization differences, and whose predicted results are not affected by removing a single image are obtained (CCNT1, NSUN5, PRPF4, RECQL4, UTP6, ZNF500). Further verification reveals that these proteins are not differentially expressed, but are closely associated with breast cancer and have great classification performance. Potential mechanism analysis shows that their co-expressed or co-located proteins and RNAs may affect their localization, leading to changes in interactions and functions that further causes breast cancer. They have the potential to help shed light on the molecular mechanisms of breast cancer and provide assistance for its early diagnosis and treatment., (© 2024. The Author(s).)

Breast cancer is most common in women, and in most cases there is no evidence of spread and the primary tumor is removed, resulting in a 'cure'. However, in 10% to 30% of these women, distant metastases recur after years to decades. This is due to breast cancer cells disseminating to distant organs and lying quiescent. This is called metastatic dormancy. Dormant cells are generally resistant to chemotherapy, hormone therapy and immunotherapy as they are non-cycling and receive survival signals from their microenvironment. In this state, they are clinically irrelevant. However, risk factors, including aging and inflammation can awaken dormant cells and cause breast cancer recurrences, which may happen even more than ten years after the primary tumor removal. How these breast cancer cells remain in dormancy is being unraveled. A key element appears to be the mesenchymal stem cells in the bone marrow that have been shown to promote breast cancer metastatic dormancy in recent studies. Indirect co-culture, direct co-culture and exosome extraction were conducted to investigate the modes of signal operation. Multiple signaling molecules act in this process including both protein factors and microRNAs. We integrate these studies to summarize current findings and gaps in the field and suggest future research directions for this field.

Background: The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. Methods: We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both in vitro and in vivo experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Results: Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both in vitro and in vivo experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. Conclusion: The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Introduction: Breast cancer (BC) is a malignant disease that occurs worldwide and poses serious health burden., Objectives: To assess the prevalence of BC burden in the Western Pacific region (WPR) from 1990 to 2019, and to predict trends from 2020 to 2044. To analyze the driving factors and put forward the region-oriented improvement., Methods: Based on the Global Burden of Disease Study 2019, BC cases, deaths, disability-adjusted life years (DALYs) cases, age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and age-standardized DALYs rate in WPR from 1990 to 2019 was obtained and analysed. Age-period-cohort (APC) model was used to analyze age, period, and cohort effects in BC, and Bayesian APC (BAPC) was used to predict trends over the next 25 years., Results: In conclusion, BC incidence and deaths in the WPR have increased rapidly over the past 30 years and are expected to continue to increase between 2020 and 2044. Among behavioral and metabolic factors, high body-mass index was the main risk factor for BC mortality in middle-income countries, whereas alcohol use was the main risk factor in Japan. Age is a key factor in the development of BC, with 40 years being the critical point. Incidence trends coincide with the course of economic development., Conclusions: The BC burden remains an essential public health issue in the WPR and will increase substantially in the future. More efforts should be made in middle-income countries to prompt the health behavior and minimize the burden of BC because these nations accounts for the majority of BC burden in the WPR., 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 © 2024. Production and hosting by Elsevier B.V.)

Breast cancer (BC) is the most commonly diagnosed malignant tumour in females worldwide. Although remarkable advances in early detection and treatment strategies have led to decreased mortality, recurrence and metastasis remain the major causes of cancer death in BC patients. Increasing evidence has demonstrated that circular RNAs (circRNAs) play critical roles in cancer progression. However, the detailed biological functions and molecular mechanisms of circRNAs in BC are unclear. The aim of this study was to investigate the possible role of circRNAs in the progression of BC. Differentially expressed circRNAs in BC were identified by integrating breast tumour-associated somatic CNV data and circRNA high-throughput sequencing. Aberrant hsa&#95;circ&#95;0007990 expression and host gene copy number were detected in BC cell lines via quantitative polymerase chain reaction (qPCR). The expression level of hsa&#95;circ&#95;0007990 in BC tissues was validated by in situ hybridization (ISH). Loss- and gain-of-function experiments were performed in vitro and in vivo, respectively, to explore the potential biological function of hsa&#95;circ&#95;0007990 in BC. The underlying mechanisms of hsa&#95;circ&#95;0007990 were investigated through MS2 RNA pull-down, RNA immunoprecipitation, RNA fluorescence in situ hybridization, immunofluorescence, chromatin immunoprecipitation and luciferase reporter assays. The levels of hsa&#95;circ&#95;0007990 were elevated in BC tissues and cell lines, an effect that was partly due to host gene copy number gains. Functional assays showed that hsa&#95;circ&#95;0007990 promoted BC cell growth. Mechanistically, hsa&#95;circ&#95;0007990 could bind to YBX1 and inhibit its degradation by preventing ubiquitin/proteasome-dependent degradation, thus enhancing the expression of the cell cycle-associated gene E2F1. Rescue experiments suggested that hsa&#95;circ&#95;0007990 promoted BC progression through YBX1. In general, our study demonstrated that hsa&#95;circ&#95;0007990 modulates the ubiquitination and degradation of YBX1 protein and further regulates E2F1 expression to promote BC progression. We explored the possible function and molecular mechanism of hsa&#95;circ&#95;0007990 in BC and identified a novel candidate target for the treatment of BC., (© 2024. The Author(s).)

BRCA2-mutated carriers have a high lifetime risk of breast cancer (BC), an early age of onset, and an increased risk of other cancers (including ovarian, pancreatic, and prostate cancer). Almost 70-80% of BRCA2-mutated BC are estrogen receptor (ER)-positive, which is a particular type of ER-positive BC that differs from sporadic ER-positive BC. This article reviews the clinicopathological features, treatment, and prognosis of ER-positive and BRCA2-mutated BC to provide a reference for clinical decision-making., (© 2024. The Author(s).)

Background: Breast cancer (BCa) is a major challenge for women's health worldwide. Ferroptosis is closely related to tumorigenesis and cancer progression. However, the prognostic value of ferroptosis-related genes in BCa remains unclear, and more accurate prognostic models are urgently needed., Methods: Gene expression profiles and clinical information of BCa patients were collected from public databases. LASSO and multivariate Cox regression analysis were utilized to construct the prognostic gene signature. Kaplan-Meier plotter, receiver operating characteristic (ROC) curves, and nomogram were used to validate the prognostic value of the gene signature. Gene set enrichment analysis was performed to explore the molecular functions and signaling pathways., Results: Differentially expressed ferroptosis-related genes between BCa samples and normal tissues were obtained. A novel five-gene signature including BCL2, SLC40A1, TFF1, APOOL, and PRAME was established for prognosis prediction. Patients stratified into high-risk or low-risk group displayed significantly different survival. Kaplan-Meier and ROC curves showed a good performance for survival prediction in different cohorts. Biological function analysis revealed that the five-gene signature was associated with cancer progression, immune infiltration, immune response, and drug resistance. Nomogram including the five-gene signature was established., Conclusion: A novel five ferroptosis-related gene signature and nomogram could be used for prognostic prediction in BCa., (© 2023. The Author(s).)

Mounting evidence indicate that cuproptosis, a novel form of programmed cell death, contributes to cancer development and progression. However, a comprehensive analysis regarding the expressions, functions, and regulatory network of cuproptosis-related genes is still lacking. In the present work, cuproptosis-related genes, upstream miRNAs and lncRNAs, and clinical data of breast cancer from TCGA database were analyzed by R language including Cox regression analysis, correlation calculation, ROC curve construction, and survival evaluation, and were further verified by public-available databases. Chemosensitivity and immune infiltration were also evaluated by online tools. SLC31A1 was significantly increased in breast cancer samples than those in normal tissues. SLC31A1 was negatively related to a favorable outcome in breast cancer, and the AUC value increased with the prolongation of follow-up time. LINC01614 and miR-204-5p were potential upstream regulators of SLC31A1. Moreover, SLC31A1 was significantly positively correlated with different immune cells infiltration, immune cell biomarkers, and immune checkpoints in breast cancer. SLC31A1 was a potential cuproptosis-related gene in breast cancer, which was significantly upregulated and was able to predict diagnosis, prognosis, chemosensitivity, and immune infiltration. LINC01640/miR-204-5p/SLC31A1 might be a significant and promising axis during cuproptosis in breast cancer., (© 2023. The Author(s).)

Endocrine therapy is the prominent strategy for the treatment of hormone-positive breast cancers. The emergence of resistance to endocrine therapy is a major health concern among hormone-positive breast cancer patients. Resistance to endocrine therapy demands the design of newer therapeutic strategies. The understanding of underlying molecular mechanisms of endocrine resistance, components of the tumor microenvironment (TME), and interaction of resistant breast cancer cells with the cellular/acellular components of the intratumoral environment are essential to formulate new therapeutic strategies for the treatment of endocrine therapy-resistant breast cancers. In the first half of the article, we have discussed the general mechanisms (including mutations in estrogen receptor gene, reregulated activation of signaling pathways, epigenetic changes, and cell cycle alteration) responsible for endocrine therapy resistance in hormone-positive breast cancers. In the latter half, we have emphasized the precise role of cellular (cancer-associated fibroblasts, immune cells, and cancer stem cells) and acellular components (collagen, fibronectin, and laminin) of TME in the development of endocrine resistance in hormone-positive breast cancers. In sum, the article provides an overview of the relationship between endocrine resistance and TME in hormone-positive breast cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yuan, Yang, Li, Zhang, Wang, Huang, Wang, Mohan, Sethi and Wang.)

The presence of large genomic rearrangements (LGRs) has been heavily investigated in breast and ovarian cancer. However, correlations between LGRs and cancer types beyond these two have not been extensively profiled, likely due to the highly inefficient methods of detecting these types of alterations. This study utilized next-generation sequencing (NGS) to analyze and classify the germline LGR profile in 17 025 cancer patients across 22 cancer types. We characterized newly identified LGRs based on predicted pathogenicity and took a closer look at genes that acquire both germline and somatic mutations within our samples. The detection method for LGRs was validated using droplet digital polymerase chain reaction (ddPCR) assay of commonly investigated LGR genes. In total, 15 659 samples from across 22 cancer types were retained for analysis after filtering. We observed that, in our cohort, the cancer types with the highest proportion of germline LGRs were ovarian cancer (4.7%), renal cell carcinoma (2.5%), breast cancer (2%), glioma (1.8%) and thyroid carcinoma (1.8%). Annotation of detected germline variants revealed several genes-MSH2, FANCA and PMS2-that contain novel LGRs. We observed co-occurrences between germline LGRs in MSH2 and somatic single nucleotide variants/insertion and deletions (SNVs/InDels) in BRCA2, KTM2B, KDM5A, CHD8, and HNF1A. Furthermore, our analysis showed that samples with pathogenic and likely pathogenic germline LGRs tended to also have higher mutational burden, chromosomal instability, and microsatellite instability ratio compared to samples with pathogenic germline SNVs/InDels. In this study, we demonstrated the prevalence of pathogenic germline LGRs beyond breast and ovarian cancer. The profiles of these pathogenic or likely pathogenic alterations will fuel further investigations and highlight new understanding of LGRs across multiple cancer types., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Chemo-photothermal/photodynamic synergistic therapy is a new effective cancer treatment method to overcome the limitations of single chemotherapy. However, the limited low photothermal conversion efficiency, the hypoxic tumor microenvironment, and premature leakage of the drug constrain their clinical applications. To address these challenges, an all-in-one biodegradable polydopamine-coated UiO-66 framework nanomedicine (DUPM) was developed to co-deliver the drug doxorubicin hydrochloride (DOX) and the excellent photothermal material MoO x nanoparticles (NPs). The results showed that DUPM exhibited good physicochemical stability and efficiently accumulated tumor tissues under pH-, glutathione-, and NIR-triggered drug release behaviour. Of note, the synthesized MoO x NPs endowed DUPM with self-supporting oxygen production and generated more reactive oxygen species ( 1 O 2 and·OH), besides, it induces Mo-mediated redox reaction to deplete excessive glutathione thus relieving tumor hypoxia to enhance PDT, further improving synergistic therapy. Meanwhile, DUPM showed strong absorption in the near-infrared range and high photothermal conversion efficiency at 808 nm (51.50%) to realize photoacoustic imaging-guided diagnosis and treatment of cancer. Compared with monotherapy, the in vivo anti-tumor efficacy results showed that DUMP exerted satisfactory tumor growth inhibition effects (94.43%) with good biocompatibility. This study provides a facile strategy to develop intelligent multifunctional nanoparticles with tumor hypoxia relief for improving synergistic therapy and diagnosis against breast cancer., 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 © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: CXCL12 is a vital factor in physiological and pathological processes, by inducing migration of multiple cells. We aimed to comprehensively detect the role of CXCL12 in breast cancer, and explore novel CXCL12-related biomarkers through integrative multi-omics analyses to build a powerful prognostic model for breast cancer patients., Methods: Immunohistochemistry analysis of the tissue microarray was performed to evaluate the correlation between CXCL12 expression levels and breast cancer patient outcomes. Combined single-nucleus and spatial transcriptomics data was used to uncover the expression distribution of CXCL12 in breast cancer microenvironment. CXCL12-related genes were identified by WGCNA analysis. Univariate Cox and LASSO regression analyses were then conducted to screen prognostic genes from above CXCL12-related genes, followed by the construction of the CXCL12-related prognostic signature, identification of risk groups, and external validation of the prognostic signature. Analyses of biological function, mutation landscape, immune checkpoint genes and immune cells, were performed to further reveal the differences between high/low-risk groups. Paired single-cell RNA-seq and bulk RNA-seq were analyzed to further disclose the association between the risk score and the complex tumor immune microenvironment. To screen potential therapeutic agents for breast cancer patients, analyses of gene-drug correlation and sensitivity to immunotherapy were conducted., Results: High expression of CXCL12 was linked with a prolonged survival in breast cancer. A total of 402 genes were identified by WGCNA analysis and 11 genes, covering VAT1L, TMEM92, SDC1, RORB, PCSK9, NRN1, NACAD, JPH3, GJA1, BMP8B and ADAMTS2 , were screened as the candidate prognostic genes. Next, the prognostic signature was built and validated using these genes to predict the outcomes of breast cancers. The high-risk group patients exhibited significantly inferior prognoses. The combination of the risk score and tumor mutational burden (TMB) had remarkably improved performance in predicting patient outcomes. Besides, high-risk group patients showed higher infiltration of M2-like macrophages. Finally, several potential anticancer drugs were identified. The high-risk group patients were more sensitive to immunotherapy but resistant to docetaxel., Conclusions: CXCL12 has important immunological implication and prognostic significance in breast cancer. The CXCL12-related prognostic model could well predict the prognosis and treatment response of breast cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gao, Fang, Yuan, Sun and Li.)

Background: The tumor-adipose microenvironment (TAME) is characterized by the enrichment of adipocytes, and is considered a special ecosystem that supports cancer progression. However, the heterogeneity and diversity of adipocytes in TAME remains poorly understood., Methods: We conducted a single-cell RNA sequencing analysis of adipocytes in mouse and human white adipose tissue (WAT). We analyzed several adipocyte subtypes to evaluate their relationship and potential as prognostic factors for overall survival (OS). The potential drugs are screened by using bioinformatics methods. The tumor-promoting effects of a typical adipocyte subtype in breast cancer are validated by performing in vitro functional assays and immunohistochemistry (IHC) in clinical samples., Results: We profiled a comprehensive single-cell atlas of adipocyte in mouse and human WAT and described their characteristics, origins, development, functions and interactions with immune cells. Several cancer-associated adipocyte subtypes, namely DPP4 + adipocytes in visceral adipose and ADIPOQ + adipocytes in subcutaneous adipose, are identified. We found that high levels of these subtypes are associated with unfavorable outcomes in four typical adipose-associated cancers. Some potential drugs including Trametinib, Selumetinib and Ulixertinib are discovered. Emphatically, knockdown of adiponectin receptor 1 (AdipoR1) and AdipoR2 impaired the proliferation and invasion of breast cancer cells. Patients with AdipoR2-high breast cancer display significantly shorter relapse-free survival (RFS) than those with AdipoR2-low breast cancer., Conclusion: Our results provide a novel understanding of TAME at the single-cell level. Based on our findings, several adipocyte subtypes have negative impact on prognosis. These cancer-associated adipocytes may serve as key prognostic predictor and potential targets for treatment in the future., (© 2023. The Author(s).)

Mounting evidence demonstrates that long noncoding RNAs (lncRNAs) have critical roles in the initiation and progression of cancer. Here, we report that small nucleolar RNA host gene 3 (SNHG3) is a key regulator of breast cancer progression. We analyzed RNA sequencing data to explore abnormally expressed lncRNAs in breast cancer. The effects of SNHG3 on breast cancer were investigated via in vitro and in vivo assays (CCK-8 assay, colony formation assay, flow cytometry assay, EdU assay, xenograft model, immunohistochemistry, and Western blot). The mechanism of SNHG3 action was explored through bioinformatics, RNA fluorescence in situ hybridization, luciferase reporter assay, RNA pull-down assay, chromatin immunoprecipitation assay and RNA immunoprecipitation assay. We found that SNHG3 expression was upregulated in breast cancer tissues and that its high expression level was associated with poor survival. We also found that high SNHG3 expression was partly induced by STAT3. Moreover, SNHG3 knockdown significantly repressed breast cancer cell growth both in vitro and in vivo . In the cytoplasm, SNHG3 facilitated the expression of Casein kinase II-A1 (CSNK2A1) by absorbing miR-485-5p and recruiting the HuR protein, participating in the malignant progression of breast cancer. Taken together, our study reveals a SNHG3-based regulatory network, which plays an oncogenic role in breast cancer and suggests that SNHG3 may serve as a potential target for the diagnosis and treatment of breast cancer.

Background: Subcellular organelle targeted nano-formulations for cancer treatment are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off-target side effects. The nucleus and mitochondria, as the main subcellular organelles, are the significant organelles responsible for maintaining cell operation and metabolism. They can be involved in many essential physiological and pathological processes such as cell proliferation, organism metabolism, intracellular transportation, and play a critical role in regulating cell biology. Meanwhile, breast cancer metastasis is one of the leading causes of death in breast cancer patients. With the development of nanotechnology, nanomaterials have been widely used in tumor therapy., Methods: We designed a subcellular organelle targeted nanostructured lipid carriers (NLC) to deliver paclitaxel (PTX) and gambogic acid (GA) to tumor tissues., Results: Due to the surface of NLC being modified by subcellular organelle targeted peptide, the PTX and GA co-loaded NLC can accurately release PTX and GA in tumor cells. This property makes NLC able to easy to enter tumor site and target the specific subcellular organelle. The modified NLC can efficiently inhibit the growth of 4T1 primary tumor and lung metastasis, which may be related to the down-regulation of matrix metalloproteinase-9 (MMP-9) and BCL-2 levels, up-regulation of E-cadherin level, and antagonized PTX-induced increase of C-C chemokine ligand 2 (CCL-2) levels by GA. Meanwhile, the synergistic anti-tumor effect of GA and PTX has also been verified in vitro and in vivo experiments., Conclusion: The subcellular organelle targeted peptide modified PTX+GA multifunctional nano-drug delivery system has a good therapeutic effect on tumors, and this study provides significant insights into the role of different subcellular organelles in inhibiting tumor growth and metastasis and inspires researchers to develop highly effective cancer therapeutic strategies through subcellular organelle targeted drugs., Competing Interests: The authors declare that they have no competing interests in this work., (© 2023 Dang et al.)

Study Objectives: This study aimed to investigate the mechanisms of a combined brief cognitive behavioral plus bright light therapy (CBT-I+Light) in women receiving chemotherapy., Methods: Women (N = 101) were randomly assigned to CBT-I+Light or treatment as usual plus relaxation audios (TAU+). Participants completed sleep diaries and wore an actigraph during the 6-week intervention period. Patient-reported outcomes were assessed at baseline, mid-point (week 3), and later (week 6). Cognitive (i.e., dysfunctional sleep beliefs, pre-sleep cognitions, and arousal) and behavioral (i.e., time in bed awake and day-to-day out-of-bedtime variability) mechanisms were examined., Results: Cognitively, both groups declined significantly in overall dysfunctional sleep beliefs from pre- to post-intervention (both p < .04); however, they did not differ on sleep-related beliefs nor pre-sleep cognitions and arousal at post-intervention (both p > .50). Dysfunctional beliefs sleep expectations subscale was lower in CBT-I+Light versus TAU+ ( p = .01). Behaviorally, CBT-I+Light reported less overall time in bed awake after the start of the intervention ( p < .05) and significantly less time in bed during the morning until the final week of the intervention period. Out-of-bedtime day-to-day variability was lower in the CBT-+Light vs TAU+ at the final intervention day., Conclusion: Mechanisms of CBT-I+Light during chemotherapy remain to be shown. Our results suggest that changes in behavioral mechanisms may be associated with sleep improvements within this cohort. Future studies should assess the role of additional mechanisms (e.g., sleep effort) within larger samples. Whilst intervention brevity is important, more potent interventions may be required to achieve robust changes in target mechanisms.

Combination therapy is an effective way to alleviate the shortcoming of monotherapy and enhances therapeutic efficacy. Herein, a distinctive hollow mesoporous silica nanoparticle (HMSNs) encapsulated with folic acid-modified bovine serum albumin (BSA-FA), denoted as HBF, was engineered for tumor targeting and dual-responsive release of loaded-therapeutic agents MD (methylene blue (MB) and doxorubicin (DOX)). The BSA molecule as a ''gatekeeper'' prevents premature drug leakage and actively unloads the cargos through BSA detachment in response to intracellular glutathione (GSH). Folic acid (FA) promotes the specific intracellular delivery of the drug to folate receptor (FR)-expressing cancer cells to improve the efficacy of chemo-photodynamic therapy (PDT). In vitro drug release profiles showed that the drug carrier could achieve pH/redox-responsive drug release from MD@HBF owing to the cleavage of the imine bonds between HMSNs-CHO and BSA-FA and BSA intramolecular disulfide bond. Additionally, a series of biological evaluations, such as cell uptake experiments, toxicity experiments, and in vivo therapeutic assays indicated that MD@HBF possesses the features of accurately targeting FR-expressing 4T1 cells to induce cells apoptosis in vitro, exhibits outstanding tumor cell synergistic killing efficiency of chemo-photodynamic therapy (combination index CI = 0.325), and inhibits tumors growth. These results demonstrated that the strategy of combining HMSNs with stimuli-responsive biodegradable protein molecules could provide a new potential direction toward the ''on-demand'' drug release for precision chemo-photodynamic therapy in cancer treatment., 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 © 2023 Elsevier B.V. All rights reserved.)

CRISPR/Cas12a has shown great potential in molecular diagnostics, but its application in sensing of microRNAs (miRNAs) was limited by sensitivity and complexity. Here, we have sensitively and conveniently detected microRNAs by reasonably integrating metal-organic frameworks ( M OFs) based bio b arcodes with CRISPR/ C as12a a ssay (designated as MBCA). In this work, DNA-functionalized Zr-MOFs were designed as the converter to convert and amplify each miRNA target into activators that can initiate the trans -cleavage activity of CRISPR/Cas12a to further amplify the signal. Such integration provides a universal strategy for sensitive detection of miRNAs. By tuning the complementary sequences modified on nanoprobes, this assay achieves subattomolar sensitivity for different miRNAs and was selective to single-based mismatches. With the proposed method, the expression of miR-21 in different cancer cells can be assessed, and breast cancer patients and healthy individuals can be differentiated by analyzing the target miRNAs extracted from serum samples, holding great potential in clinical diagnosis.

Mesenchymal stromal cells (MSCs) play an important role in the development of human cancer. Meanwhile, exosomes released by MSCs can mediate cell-cell communication by delivering microRNAs (miRNAs/miRs). Hence, this study aimed to explore the role of bone marrow mesenchymal stromal cell (BMSC)-derived exosomal miR-551b-3p in breast cancer. In this study, we found that upregulation of miR-551b-5p suppressed the proliferation and migration and induced the apoptosis of breast cancer cells via downregulating tripartite motif-containing protein 31 (TRIM31). In addition, miR-551b-5p could be transferred from BMSCs to breast cancer cells via exosomes; BMSC-derived exosomal miR-551b-3p suppressed the proliferation and migration and promoted the apoptosis and oxidative stress of MDA-MB-231 cells via inhibiting TRIM31. Furthermore, a xenograft mouse model was used to explore the role of BMSC-derived exosomal miR-551b-3p in vivo. We found that BMSC-derived exosomal miR-551b-3p inhibited tumor growth in a mouse xenograft model of breast cancer in vivo. Collectively, these findings indicated that BMSC-derived exosomal miR-551b-3p could suppress the development of breast cancer via downregulating TRIM31. Thus, miR-551b-3p could serve as a potential target for the treatment of breast cancer., (© 2022. The Author(s) under exclusive licence to Japan Human Cell Society.)

Cancer immunotherapy is an attractive approach for antigen-specific T cell-mediated antitumor therapy, especially for the induction of cytotoxic T lymphocytes (CTLs). An human leukocyte antigen (HLA)-A2-restricted melanoma-associated antigen-A11 (MAGE-A11) peptide was developed that exhibited a potent capacity to induce cytotoxicity towards MAGE-A11-positive breast cancer cells by activating CTLs. However, this antitumor immune response can be suppressed by inhibitory pathways. Programmed death-1 (PD-1) and T cell immunoglobulin domain and mucin domain 3 (TIM-3) pathways are two important pathways involved in the tumor-mediated immune suppression. The present study aimed to augment the efficacy of MAGE-A11 antigen-specific CTLs via blocking PD-1 and TIM-3. The results showed that the expression levels of PD-1 and TIM-3 were unregulated during T cell induction, expansion and target cell killing. Blockade of PD-1 and TIM-3 modulated T cell proliferation, transformation and survival. In addition, treatment of cells with antibodies against PD-1 and TIM-3 enhanced the cytotoxicity of MAGE-A11 antigen-specific CTLs against breast cancer cells. The aforementioned findings suggested that MAGE-A11 antigen-specific CTLs accompanied by PD-1 and TIM-3 blockade could be considered as a potential therapy approach for breast cancer., (Crown Copyright © 2022. Published by Elsevier Masson SAS. All rights reserved.)

Background: Insomnia and fatigue symptoms are common in breast cancer. Active cancer treatment, such as chemotherapy, appears to be particularly disruptive to sleep. Yet, sleep complaints often go unrecognised and under treated within routine cancer care. The abbreviated delivery of cognitive behavioral therapy for Insomnia (CBTI) and bright light therapy (BLT) may offer accessible and cost-effective sleep treatments in women receiving chemotherapy for breast cancer., Methods: The Sleep, Cancer and Rest (SleepCaRe) Trial is a 6-month multicentre, randomized, controlled, 2 × 2 factorial, superiority, parallel group trial. Women receiving cytotoxic chemotherapy for breast cancer at tertiary Australian hospitals will be randomly assigned 1:1:1:1 to one of four, non-pharmacological sleep interventions: (a) Sleep Hygiene and Education (SHE); (b) CBTI; (c) BLT; (d) CBT-I + BLT combined and simultaneously delivered. Each sleep intervention is delivered over 6 weeks, and will comprise an introductory session, a mid-point phone call, and regular emails. The primary (insomnia, fatigue) and secondary (health-related quality of life, rest activity rhythms, sleep-related impairment) outcomes will be assessed via online questionnaires at five time-points: baseline (t0, prior to intervention), mid-point intervention (t2, Week 4), post-intervention (t3, Week 7), 3-months (t4, Week 18), and 6-months follow-up (t5, Week 30)., Conclusions: This study will report novel data concerning the comparative and combined efficacy of CBT-I and BLT during chemotherapy. Findings will contribute to the development of evidence-based early sleep and fatigue intervention during chemotherapy for breast cancer. Clinical trial information Registered with the Australian New Zealand Clinical Trials Registry (http://anzctr.org.au/), Registration Number: ACTRN12620001133921., Competing Interests: Declaration of Competing Interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Pathological complete response (pCR) is considered a surrogate for favorable survival in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NACT), which is the goal of NACT. This study aimed to develop and validate a nomogram for predicting the pCR probability of BC patients after NACT based on the clinicopathological features., Methods: A retrospective analysis of 527 BC patients treated with NACT between January 2018 and December 2021 from two institutions was conducted. Univariate and multivariate logistic regression analyses were performed to select the most useful predictors from the training cohort (n = 225), and then a nomogram model was developed. The performance of the nomogram was evaluated with respect to its discrimination, calibration, and clinical usefulness. Internal validation and external validation were performed in an independent validation cohort of 96 and 205 consecutive BC patients, respectively., Results: Among the 18 clinicopathological features, five variables were selected to develop the prediction model, including age, American Joint Committee on Cancer (AJCC) T stage, Ki67 index before NACT, human epidermal growth factor receptor 2 (HER2), and hormone receptor (HR) status. The model showed good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.825 (95% CI, 0.772 to 0.878) in the training cohort, and 0.755 (95% CI, 0.658 to 0.851) and 0.79 (95% CI, 0.724 to 0.856) in the internal and external validation cohorts, respectively. The calibration curve presented good agreement between prediction by nomogram and actual observation, and decision curve analysis (DCA) indicated that the nomogram had good net benefits in clinical scenarios., Conclusion: This study constructed a validated nomogram based on age, AJCC T stage, Ki67 index before NACT, HER2, and HR status, which could be non-invasively applied to personalize the prediction of pCR in BC patients treated with NACT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qian, Yang, Zhou, Hu, Zhang, Ren and Qu.)

Background: Doxorubicin (DOX) resistance remains a major challenge for adriamycin-based treatment of breast cancer (BC). Transforming growth factor β (TGF-β) has been reported to contribute to drug resistance. Although the role of long noncoding RNAs (LncRNAs) in cancer progression has been widely studied, its effect on TGF-β-induced resistance remains limited. This study aimed to investigate the role of LncRNA on the regulation of TGF-β-induced drug resistance., Methods: Cell counting kit-8 (CCK-8) and an EdU assay were used to evaluate cell viability and proliferation. The level of LncRNA mRNA expression in BC tissues and cells was examined by quantitative real-time PCR. Changes in epithelial-mesenchymal transition (EMT) and cell apoptosis were quantified by Western blot and immunofluorescence., Results: TGF-β induced EMT and promoted DOX resistance. LncRNA urothelial carcinoma-associated 1(lncRNA UCA1) associated with TGF-β was upregulated in BC cells and tissues. LncRNA UCA1 silencing enhanced sensitivity to DOX decreased cellular proliferation and increased apoptosis in BC cells. The effect of TGF-β on EMT and DOX resistance disappeared following a lncRNA UCA1 knockdown., Conclusions: These findings suggest that lncRNA-UCA1, a mediator of TGF-β signaling, could predispose BC patients to EMT and DOX resistance.

The tumor-adipose microenvironment (TAME) is a universal microecosystem, that is characterized by the dysfunction of lipid metabolism, such as excessive free fatty acids (FFAs). Macrophages are the most abundant immune cell type within TAME, although their diversity in the TAME is not clear. We first reveal that infiltration of M2-like macrophages in the TAME is associated with poor survival in breast cancer. To explore lipid-associated alterations in the TAME, we also detected the levels of FFAs transporters including fatty acid binding proteins (FABPs) and fatty acid transport protein 1 (FATP1). The results indicated that expression of fatty acid transporters in the TAME is tightly linked to the function of macrophages and predicts survival in breast cancer. To explore the impact of FFAs transporters on the function of macrophages, we performed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. Consequently, we identified a special subpopulation of macrophages defined as lipid-associated macrophages (LAMs), highly expressed macrophage markers (CD163, SPP1 and C1QC), genes involved in lipid metabolism (FABP3, FABP4, FABP5, LPL and LIPA) and some lipid receptors (LGALS3 and TREM2). Functionally, LAMs were characterized by a canonical functional signature of M2-like macrophages, lipid accumulation and enhancing phagocytosis, and they were mostly distributed in tumor-adipose junctional regions. Finally, the allograft cancer mouse models confirmed that LAMs depletion in the TAME synergizes the antitumorigenic effects of anti-PD1 therapy. In summary, we defined a novel subtype of macrophages in the TAME, that has unique features and clinical outcomes., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Study Objectives: Sleep problems are common during chemotherapy for breast cancer (BC). We evaluated whether combined brief cognitive behavioral and bright light therapy (CBT-I + Light) is superior to treatment as usual with relaxation audio (TAU+) for insomnia symptoms and sleep efficiency (primary outcomes)., Methods: We randomized women receiving intravenous chemotherapy, stratified by tumor stage and insomnia severity index, to 6-week CBT-I + Light or TAU+. CBT-I + Light included 1 in-person session, 1 telephone call, 7 emails, and 20 min bright light (BL) each morning. TAU+ comprised usual treatment and two emails with relaxation audio tracks. Patient-reported outcomes were assessed at baseline, midpoint (week 3), post (week 6), and 3-month follow-up., Results: Women (N = 101) were randomly assigned to CBT-I + Light or TAU+. The CBT-I + Light group showed significantly greater improvement in insomnia symptoms than the TAU+ group (-5.06 vs -1.93, p = .009; between-group effect size [ES] = .69). At 3-month follow-up, both groups were lower than baseline but did not differ from each other (between-group ES = .18, p = .56). CBT-I + Light had higher patient-reported sleep efficiency than TAU+ immediately after the start of intervention (p = .05) and significantly greater improvement in fatigue (between-group ES = .59, p = .013) and daytime sleep-related impairment (between-group ES = .61, p = .009) than the TAU+ group., Conclusions: CBT-I + Light had a clinically significant impact on insomnia and fatigue with moderate ESs. Results support offering cognitive behavioral therapy for insomnia and BL therapy during chemotherapy for BC to help manage sleep and fatigue., Clinical Trial: Australian New Zealand Clinical Trials Registry (http://anzctr.org.au/). Registration number: ACTRN12618001255279., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Multidrug resistance (MDR) of tumors has been recognized as an important cause of chemotherapy failure, which is responsible for about 90% of cancer deaths. Therefore, it is desirable to develop a highly effective strategy to reverse tumor MDR for rebuilding the sensitivity of tumor cells towards chemodrugs. Here, self-assembled DNAzyme nanoflowers (NFs) constructed by rolling circle amplification (RCA) strategy were applied in doxorubicin (Dox) delivery for efficiently ablating Dox-resistant breast cancer. The encoded multiple DNAzymes could catalytically cleave P-glycoprotein (P-gp) mRNA which assists the efflux of chemodrugs, for reversing the MDR. The in vitro and in vivo results showed that the P-gp DNAzymes NFs not only had a high drug-loading capacity (69.21%) and acid-triggered biodegrade ability, but also effectively suppressed the expression of P-gp for reversing MDR of the tumor. Therefore, the DNAzyme-based drug delivery nanoplatform would be a promisingstrategyfor reversing MDR in cancer therapy., 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 © 2021 Elsevier Inc. All rights reserved.)

Objective: This study was designed to critically evaluate the effect of home-based walking on cancer-related fatigue (CRF) in patients with breast cancer (BC) receiving anticancer treatment., Data Sources: Eight databases were systematically searched from inception to March 2021 for randomized controlled trials (RCTs) without language restrictions., Study Selection: Two reviewers (Y.Y. and Z.N.) scanned the titles and abstracts and then read the full texts of potentially eligible trials to screen the literature. Inclusion criteria were studies of home-based walking (HBW) intervention in adult patients with BC, using fatigue as a primary or secondary outcome, and containing extractable fatigue scores., Data Extraction: Two reviewers (Y.Y. and Z.N.) critically and independently assessed the risk of bias using Cochrane Collaboration criteria and extracted correlated data using the designed extraction form. The standardized mean difference (SMD) was used when the outcome assessment tools were different. All of the analyses were performed using Review Manager 5.3., Data Synthesis: Eight RCTs including 764 patients (HBW: 377, control: 387) meeting the inclusion criteria for the meta-analysis were identified. HBW had a significant effect on CRF in patients with BC receiving multiple anticancer treatments (SMD=-0.61; 95% confidence interval [CI], -0.86 to -0.36; P<.001). HBW without other exercises (SMD=-0.83; 95% CI, -1.39 to -0.27; P=.003), walking for a gradually increased duration (SMD=-1.24; 95% CI, -2.20 to -0.28; P=.010), and no restrictions on walking intensity (SMD=-1.03; 95% CI, -1.75 to -0.31; P=.005) demonstrated substantial effects on CRF. Of the 8 included studies, only 3 reported adverse events., Conclusions: HBW can be considered as an alternative therapy for relieving CRF in patients with BC undergoing anticancer treatment., (Copyright © 2021 The American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: To unravel mechanisms of miR-204-5p in breast cancer (BC) cells., Methods: miR-204-5p expression level in BC cell lines was measured by qRT-PCR. Putative binding sites of miR-204-5p on the 3'-untranslated region of PRR11 were predicted by the bioinformatics method and verified by the dual-luciferase method. Protein and mRNA levels of PRR11 in BC were determined by western blot and qRT-PCR. The association between two genes was analyzed by correlation analysis. Cancer cell functions were evaluated through CCK8, flow cytometry, and Transwell approaches., Results: Significant downregulation of miR-204-5p was observed in BC tissue and cells. Cell functional experiments showed the inhibition of miR-204-5p on cell behaviors and cell cycle. PRR11 was the downstream target of miR-204-5p. Inhibition of RPP11 could reverse the impacts of the miR-204-5p inhibitor on cell functions of BC., Conclusion: Our study revealed that the miR-204-5p/PRPP11 axis suppressed BC progression, which may provide a novel insight into the regulatory roles of miR-204-5p., Competing Interests: The authors do not have any possible conflicts of interest., (Copyright © 2022 Qunxue Su et al.)

Numerous studies have manifested that cicular RNA (circRNA) is closely associated with the development of breast cancer (BC), but the specific mechanism has not been fully clarified. The purpose of this study was to investigate the effect of circCNOT2 on BC invasion, migration and epithelial mesenchymal transition (EMT) and its potential molecular mechanism. The results assured that circCNOT2 and Twist Family BHLH Transcription Factor (TWIST1) were elevated in BC, while microrNA (miR)-409-3p was reduced. CircCNOT2 was positively correlated with TWIST1 and negatively correlated with miR-409-3p. Elevated circCNOT2 is associated with poor prognosis of BC. Knockdown circCNOT2 or augmented miR-409-3p could promote apoptosis but repress proliferation, invasion, migration and EMT of BC cells. In addition, overexpression of circCNOT2 or TWIST1 accelerated BC invasion, migration and EMT, which could be reversed by simultaneous transfection of miR-409-3p-mimic. Further dual luciferase reporting and RNA-pull down assay clarified that circCNOT2 acted as a competing endogenous RNA of miR-409-3p to mediate TWIST1 expression. In conclusion, the results of this study suggest that circCNOT2 affects the biological behavior of BC via regulating the miR-409-3p/TWIST1 axis, and may be applied as a potential therapeutic target for BC later.

Ethnopharmacological Relevance: Cimicifuga dahurica (Turcz.) Maxim (C. dahurica) has a long history of treating breast cancer. From the Qing Dynasty to the Tang Dynasty and even earlier, C. dahurica has been documented in the treatment of breast carbuncle (Breast cancer is classified as breast carbuncle in Chinese medicine). In traditional prescriptions such as "Sheng Ge Decoction", "Sheng Ma Powder" and "Breast Carbuncle Pill", as the main medicine, C. dahurica plays an important role. At present, the systematic studies on the in vitro and in vivo effects of Cimicifuga against breast cancer are rare, especially the C. dahurica., Aim of the Study: In this article, we evaluated the in vitro activity and in vivo effects of CREE (extract of the root of C. dahurica) against breast cancer, and discussed the possible mechanism of CREE in promoting breast cancer cell apoptosis., Materials and Methods: The main component in the CREE was analyzed by HPLC. The effects of CREE on the proliferation, migration and invasion of human breast cancer cells were evaluated through SRB, colony assay, LDH release, wound healing and transwell assay. The pro-apoptotic effect of CREE was investigated in Hochest33342 and Annexin V-FITC/PI assay. To verify the results of CREE in vivo effects, we applied nude mice subcutaneous xenograft experiments. The possible mechanism of CREE treating breast cancer was investigated through mitochondrial membrane potential and western blot experiments., Results: CREE contains cycloartane triterpene saponins. CREE can significantly inhibit the proliferation, migration and invasion of human breast cancer MCF-7 and MDA-MB-231 cells in vitro and it can effectively inhibit the growth of MDA-MB-231 cell subcutaneous tumors in vivo. Besides, we also found that CREE up-regulated the expression levels of Bax, caspase-9/3 and cytochrome C, and down-regulated the expression of Bcl-2. Therefore, regulation of the mitochondrial pathway may be one of the mechanisms by which CREE promotes breast cancer cell apoptosis., Conclusions: CREE exhibits sufficient anti-breast cancer activity in vivo and in vitro, this study provides persuasive evidence for the further research and development of C. dahurica., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure-response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure-efficacy and -safety relationships and support the approved SC dosing regimen., Methods: Population pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression., Results: SC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest., Conclusion: The approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit-risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab., (© 2021. The Author(s).)

Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Multiple common variants identified by genome-wide association studies have shown limited evidence of the risk of breast cancer in Chinese individuals. In this study, we aimed to uncover the relationship between estrogen levels and the genetic polymorphism of estrogen metabolism-related enzymes in breast cancer (BC) and establish a risk prediction model composed of estrogen-metabolizing enzyme genes and GWAS-identified breast cancer-related genes based on a polygenic risk score., Methods: Unrelated BC patients and healthy subjects were recruited for analysis of estrogen levels and single nucleotide polymorphisms (SNPs) in genes encoding estrogen metabolism-related enzymes. The polygenic risk score (PRS) was used to explore the combined effect of multiple genes, which was calculated using a Bayesian approach. An independent sample t-test was used to evaluate the differences between PRS scores of BC and healthy subjects. The discriminatory accuracy of the models was compared using the area under the receiver operating characteristic (ROC) curve., Results: The estrogen homeostasis profile was disturbed in BC patients, with parent estrogens (E1, E2) and carcinogenic catechol estrogens (2/4-OHE1, 2-OHE2, 4-OHE2) significantly accumulating in the serum of BC patients. We then established a PRS model to evaluate the role of SNPs in multiple genes. PRS model 1 (M1) was established from SNPs in 6 GWAS-identified high risk genes. On the basis of M1, we added SNPs from 7 estrogen metabolism enzyme genes to establish PRS model 2 (M2). The independent sample t-test results showed that there was no difference between BC and healthy subjects in M1 (P = 0.17); however, there was a significant difference between BC and healthy subjects in M2 (P = 4.9*10 - 5 ). The ROC curve results showed that the accuracy of M2 (AUC = 62.18%) in breast cancer risk identification was better than that of M1 (AUC = 54.56%)., Conclusion: Estrogen and related metabolic enzyme gene polymorphisms are closely related to BC. The model constructed by adding estrogen metabolic enzyme gene SNPs has a good predictive ability for breast cancer risk, and the accuracy is greatly improved compared with that of the PRS model that only includes GWAS-identified gene SNPs.

Breast cancer (BC) is the most common malignancy among women. Mesenteric estrogen-dependent adipogenesis gene (MEDAG) was first reported as a novel adipogenic gene, and its involvement and mechanism in visceral adiposity were analyzed. However, the role of MEDAG in BC is unclear. The biological roles and corresponding mechanisms were investigated in vitro and in vivo. We found that MEDAG was highly expressed in BC samples and that a high MEDAG expression was correlated with clinicopathological characteristics and poor survival in BC patients. MEDAG knockdown inhibited cell proliferation, invasion, and migration; triggered epithelial-to-mesenchymal transition (EMT); and enhanced epirubicin sensitivity in vitro. The opposite results were observed in MEDAG-overexpressing cells. The inhibition of MEDAG suppressed tumor growth and metastasis in vivo. Mechanistically, MEDAG knockdown led to decreased phosphorylation levels of AKT, increased levels of p-AMPK, and reduced levels of p-mTOR, while the overexpression of MEDAG had the opposite effects. Moreover, the activation of p-AKT and inhibition of p-AMPK restored the effect of MEDAG on EMT and chemosensitivity in BC cell lines, indicating that MEDAG functions as an oncogene by regulating the AKT/AMPK/mTOR pathway. MEDAG regulates BC progression and EMT via the AKT/AMPK/mTOR pathway and reduces chemosensitivity in BC cells. Therefore, MEDAG is a promising target for BC.

Background: A growing number of studies have shown that long non-coding RNAs (lncRNAs) play an important role in the occurrence and development of tumors. In this study, we explored the function and molecular mechanism of lncRNA SPINT1-AS1 in breast cancer progression., Methods: A total of 30 patients and 25 healthy controls were enrolled to detect the expression of SPINT1-AS1 in the serum by RT-qPCR. CCK-8 assay, clone formation assay, EdU assay, Transwell assay, Flow cytometry for apoptosis assay and wound healing assays were used to explore the effects of SPINT1-AS1 on the proliferation and migration of breast cancer cells. Bioinformatics analysis were used to enrich the downstream target genes and related pathways of miRNAs interacting with SPINT1-AS1, construct a competitive endogenous RNA (ceRNA) network diagram., Results: SPINT1-AS1 is up-regulated in the serum of breast cancer patients and breast cancer cell lines. The proliferation and migration ability of breast cancer cells were decreased significantly after SPINT1-AS1 knockdown, and it may inhibit its expression by sponging miR-let-7a/b/i-5p, thereby promoting breast cancer progression., Conclusions: SPINT1-AS1 can promote the proliferation and migration of breast cancer cells by regulating miR-let-7a/b/i-5p, suggesting that it may be an important regulator of breast cancer progression., (Copyright © 2020. Published by Elsevier GmbH.)

Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that retains the antitumor effects of trastuzumab while also delivering the cytotoxic antimicrotubule agent, DM1, directly to tumor cells that overexpress human epidermal growth factor receptor 2. The pharmacokinetic (PK) profile of T-DM1 has been well characterized in Western, Asian, and Japanese patients; this single-center, phase I study (NCT03153163) examined the PK of T-DM1 and safety specifically in Chinese patients., Methods: Patients with locally advanced or metastatic breast cancer, previously treated with trastuzumab and a taxane, received open-label T-DM1 at 3.6 mg/kg every 3 weeks. Serum T-DM1 and total trastuzumab, and plasma DM1 were evaluated, and PK parameters were calculated using standard noncompartmental approaches. Adverse events (AEs) were assessed, and immunogenicity was evaluated by measuring antidrug antibodies to T-DM1., Results: Among 11 Chinese patients, mean (±standard deviation) PK parameters (maximum serum concentration, 77.6 ± 17.4 μg/mL; clearance 11.0 ± 2.6 mL/d/kg; terminal half-life 3.8 ± 1.0 days) were similar to those previously reported in Western and Japanese patients. One patient transiently developed antidrug antibodies, which did not appear to influence safety or PK. T-DM1 was generally well tolerated. Grade 3-4 AEs occurred in 7 patients (63.6%) and serious AEs occurred in 4 patients (36.4%). Platelet count decrease was the most common all-grade AE (10/11; 90.9%), grade 3-4 AE (5/11; 45.5%), and serious AE (3/11; 27.3%), but did not appear to be associated with any clinically significant bleeding events., Conclusions: T-DM1 PK in Chinese patients was consistent with those in global and Asian populations, supporting its use in patients with advanced human epidermal growth factor receptor 2-positive breast cancer following progression on trastuzumab and a taxane. The safety profile of T-DM1 was consistent with prior experience.

High-efficiency cancer treatment remains the main challenge at present. In this study, a mesoporous platinum nanoparticle- (mesoPt) based nanoplatform is exported for effective tumor treatment, integrating computed tomography (CT) imaging, photothermal conversion, and chemotherapeutic drug delivery capabilities. Mesoporous platinum nanoparticles are facilely synthesized by using Pluronic F127 as a structure-directing agent without seeds or organic reagents and have a spherical structure and uniform diameter of 94 nm. The surface of the mesoPt is modified with polyethylene glycol (PEG), and the prepared mesoPt-PEG shows excellent biocompatibility. Doxorubicin (Dox)-loaded PEG@Pt (PEG@Pt/Dox) is further prepared by electrostatic adsorption and the drug-loading capacity is as high as 25%. In vitro studies demonstrate that Dox can be controllably released from PEG@Pt/Dox in pH 5.5 phosphate buffered solution (PBS). Confocal imaging verifies that PEG@Pt/Dox can efficiently enter Dox-resistant breast cancer cells (MCF-7/ADR), deliver Dox into the cytoplasm when incubated for 1 h or 12 h, and release Dox into the nucleus when incubation is prolonged to 24 h. Cell transmission electron microscopy and flow cytometry also confirm that PEG@Pt/Dox could be internalized by cells. Upon irradiation by an 808 nm laser, the anticancer effect of PEG@Pt/Dox is significantly improved and kills approximately 84% of cancer cells when the concentration of Dox is 8 μg/mL. The killing efficacy of MCF-7/ADR cells is significantly higher in the combination group than in the monochemotherapy group. Hence, multifunctional nanoplatform PEG@Pt/Dox presents an effective strategy to realize efficient combination of chemotherapy and photothermals for drug-resistant cancer., 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 © 2020 Elsevier Inc. All rights reserved.)

MicroRNA-142-3p (miR-142-3p) was previously investigated in various cancers, whereas, it's role in breast cancer (BC) remains far from understood. In this study, we found that miR-142-3p was markedly decreased both in cell lines and BC tumor tissues. Elevated miR-142-3p expression suppressed growth and metastasis of BC cell lines via gain-of-function assay in vitro and in vivo. Mechanistically, miR-142-3p could regulate the ras-related C3 botulinum toxin substrate 1 (RAC1) expression in protein level, which simultaneously suppressed the epithelial-to-mesenchymal transition related protein levels and the activity of PAK1 phosphorylation, respectively. In addition, rescue experiments revealed RAC1 overexpression could reverse tumor-suppressive role of miR-142-3p. Our results showed miR-142-3p could function as a tumor suppressor via targeting RAC1/PAK1 pathway in BC, suggesting a potent therapeutic target for BC treatment., (© 2019 Wiley Periodicals, Inc.)

Background: Women with breast cancer experience a significantly higher prevalence of sleep disturbance and insomnia than the general population. The experience of persistent sleep disturbance places these women at a higher risk of psychological and physical morbidity and a reduced quality of life. Treatment for sleep in this population is not part of routine care and is often managed inadequately. This randomised controlled trial will examine the combined effects of cognitive behavioural therapy (CBT) and bright light therapy (BLT) on the symptoms of insomnia, fatigue and mental health., Method/design: Women diagnosed with breast cancer who receive intravenous chemotherapy treatment at a quaternary referral metropolitan cancer centre in Melbourne, Australia, will be recruited. Recruitment will occur after diagnosis and prior to completion of chemotherapy. Eligible women will be randomised to the combined CBT and BLT intervention (CBT+) or relaxation audio-enhanced treatment as usual (TAU+). The CBT+ group will receive one face-to-face session on sleep strategies, one subsequent telephone call, and seven email packages containing CBT-based information and strategies. CBT+ participants will also wear Luminette® light glasses for 20 min each morning for the 6-week duration of the intervention. Women in TAU+ will receive two relaxation audio tracks via email. Outcomes will be measured at multiple points throughout the 6 weeks. Primary outcomes will be symptoms of insomnia and sleep efficiency, measured using the Insomnia Severity Index and a self-reported sleep diary. Secondary outcomes include objective measures of sleep assessed using the ActiGraph wGT3X-BT, and sleep-related complaints, fatigue and mental health, all assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS). Data will also be collected on potential treatment moderators and mechanisms and adherence to treatment. There will be 3-month follow-up measurements of insomnia symptoms, fatigue, sleep-related impairment, sleep disturbance, depression and anxiety., Discussion: This is the first randomised controlled trial to combine CBT and BLT for the treatment of sleep disturbance in women with breast cancer. This novel design addresses the multiple causal factors for sleep complaints in this population. Results from this trial will advance knowledge in this field and may have important clinical implications for how best to treat sleep disturbance and insomnia in this population. If effective, the largely email-based format of the intervention would allow for relatively easy translation., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12618001255279. Retrospectively registered on 25 July 2018.

Although observational studies have reported a positive association between obstructive sleep apnea syndrome (OSAS) and breast cancer (BC) risk, causality remains inconclusive. We aim to explore whether OSAS is associated with etiology of BC by conducting a two-sample Mendelian randomization (MR) study in a Chinese population and Asian population from the Breast Cancer Association Consortium (BCAC). We found a detrimental causal effect of OSAS on BC risk in the primary analysis of our samples (IVW OR, 2.47 for BC risk per log-odds increment in OSAS risk, 95% CI = 1.86-3.27; P = 3.6×10 -10 ). This was very similar to results of the direct observational case-control study between OSAS and BC risk (OR = 2.80; 95% CI = 2.24-3.50; P =1.4×10 -19 ). Replication in the Asian population of the BCAC study also supported our results (IVW OR, 1.33 for BC risk per log-odds increment in OSAS risk, 95% CI = 1.13-1.56; P = 0.0006). Sensitivity analyses confirmed the robustness of our findings. We provide novel evidence that genetically determined higher risk of OSAS has a causal effect on higher risk of BC. Further studies focused on the mechanisms of the relationship between OSAS and breast carcinogenesis are needed.

Aims: Baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) plays vital roles in carcinogenesis by influencing cell division and proliferation and by inhibiting apoptosis. However, the prognostic significance of BIRC5 remains unclear in breast cancer., Methods: BIRC5 expression and methylation status were evaluated using the Oncomine and The Cancer Genome Atlas (TCGA) databases. The relevance between BIRC5 and different clinicopathological features as well as survival information was analyzed using the bc-GenExMiner database and Kaplan-Meier Plotter. BIRC5-drug interaction network was obtained using the Comparative Toxicogenomics Database., Results: Based on the results from databases and own hospital data, BIRC5 was higher expressed in different breast cancer subtypes compared with the matched normal individuals. Hormone receptors were negatively correlated with BIRC5 expression, whereas the Scarff-Bloom-Richardson (SBR) grade, Nottingham Prognostic Index (NPI), human epidermal growth factor receptor-2 (HER-2) status, basal-like status, and triple-negative status were positively related to BIRC5 level in breast cancer samples with respect to normal tissues. High BIRC5 expression was responsible for shorter relapse-free survival, worse overall survival, reduced distant metastasis free survival, and increased risk of metastatic relapse event. BIRC5-drug interaction network indicated that several common drugs could modulate BIRC5 expression. Furthermore, a positive correlation between BIRC5 andcell-division cycle protein 20 (CDC20) gene was confirmed., Conclusion: BIRC5 may be adopted as a promising predictive marker and potential therapeutic target in breast cancer. Further large-scale studies are needed to more precisely confirm the value of BIRC5 in treatment of breast cancer., (© 2020 The Author(s).)