Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature

Introduction: Breast cancer is the most common cancer in women worldwide. The association between body mass index (BMI) and breast cancer risk has been paid more attention in the past few years, but the findings are still controversial. To obtain a more reliable conclusion, we performed a dose–response meta-analysis on 12 prospective cohort studies comprising 22,728,674 participants. Methods: Linear and nonlinear trend analyses were conducted to explore the dose–response relationship between BMI and breast cancer risk. The summary relative risk (SRR) and 95% confidence intervals (CIs) were used to evaluate the cancer risk. Results: The overall results showed a weak positive association between a 5-unit increase in BMI and breast cancer risk, indicating that a 5 kg/m² increase in BMI corresponded to a 2% increase in breast cancer risk (SRR: 1.02, 95% CI: 1.01–1.04, p<0.001). Notably, further subgroup meta-analysis found that higher BMI could be a protective factor of breast cancer risk for premenopausal women (SRR: 0.98, 95% CI: 0.96–0.99, p<0.001). In addition, the dose–response result demonstrated that there was a linear association between BMI and breast cancer risk (P_nonlinearity=0.754). Conclusion: In summary, this dose–response meta-analysis of prospective cohort studies showed that every 5 kg/m2 increase in BMI corresponded to a 2% increase in breast cancer risk in women. However, higher BMI could be a protective factor in breast cancer risk for premenopausal women. Further studies are necessary to verify these findings and elucidate the pathogenic mechanisms.

 Background: The flavonoid baicalein, a historically used Chinese herbal medicine, shows a wide range of biological and pharmaceutical effects, among which its potent antitumor activity has raised great interest in recent years. However, the molecular mechanism involved in the antimetastatic effect of baicalein remains poorly understood. This study aimed to verify the inhibitory effects of baicalein on metastasis of MDA-MB-231 human breast cancer cells both in vitro and in vivo, as well as to investigate the related mechanisms. Methods: MTT assay was used to examine the inhibition of baicalein on proliferation of MDA-MB-231 cells. Wound healing assay and the in vitro invasion assay was carried out to investigate the effects of baicalein on migration and invasion of MDA-MB-231 cells, respectively. In order to explore the effects of baicalein on tumor metastasis in vivo, xenograft nude mouse model of MDA-MB-231 cells was established. Animals were randomly divided into four groups (control, therapy group, and low-dose and high-dose prevention group, n=6), and treated with baicalein as designed. Following sacrifice, their lungs and livers were collected to examine the presence of metastases. qRT-PCR and Western blot were performed to study the effects of baicalein on expression of SATB1, EMT-related molecules, and Wnt/β-catenin signaling components of MDA-MB-231 cells as well as the metastatic tissue. Effects of baicalein on the expression of target proteins in vivo were also analyzed by immunohistochemistry. Results: Our results indicated that baicalein suppressed proliferation, migration, and invasion of MDA-MB-231 cells in a time- and dose-dependent manner. Based on assays carried out in xenograft nude mouse model, we found that baicalein inhibited tumor metastasis in vivo. Furthermore, baicalein significantly decreased the expression of SATB1 in MDA-MB-231 cells. It suppressed the expression of vimentin and SNAIL while enhancing the expression of E-cadherin. Baicalein also downregulated the expression of Wnt1 and β-catenin proteins and transcription level of Wnt/β-catenin-targeted genes. Conclusion: Our results demonstrate that baicalein has the potential to suppress breast cancer metastasis, possibly by inhibition of EMT, which may be attributed to downregulation of both SATB1 and the Wnt/β-catenin pathway. Taken together, baicalein may serve as a promising drug for metastasis treatment of breast cancer.

Background: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Current treatment options are limited and often ineffective. CAR T cell therapy has shown success in treating hematologic malignancies, and there is growing interest in its potential application in solid tumors, including GBM. However, current CAR T therapy lacks clinical efficacy against GBM due to tumor-related resistance mechanisms and CAR T cell deficiencies. Therefore, there is a need to improve CAR T cell therapy efficacy in GBM. Methods: We conducted large-scale CRISPR interference (CRISPRi) screens in GBM cell line U87 MG cells co-cultured with B7-H3 targeting CAR T cells to identify genetic modifiers that can enhance CAR T cell-mediated tumor killing. Flow cytometry-based tumor killing assay and CAR T cell activation assay were performed to validate screening hits. Bioinformatic analyses on bulk and single-cell RNA sequencing data and the TCGA database were employed to elucidate the mechanism underlying enhanced CAR T efficacy upon knocking down the selected screening hits in U87 MG cells. Results: We established B7-H3 as a targetable antigen for CAR T therapy in GBM. Through large-scale CRISPRi screening, we discovered genetic modifiers in GBM cells, including ARPC4, PI4KA, ATP6V1A, UBA1, and NDUFV1, that regulated the efficacy of CAR T cell-mediated tumor killing. Furthermore, we discovered that TNFSF15 was upregulated in both ARPC4 and NDUFV1 knockdown GBM cells and revealed an immunostimulatory role of TNFSF15 in modulating tumor-CAR T interaction to enhance CAR T cell efficacy. Conclusions: Our study highlights the power of CRISPR-based genetic screening in investigating tumor-CAR T interaction and identifies potential druggable targets in tumor cells that confer resistance to CAR T cell killing. Furthermore, we devised targeted strategies that synergize with CAR T therapy against GBM. These findings shed light on the development of novel combinatorial strategies for effective immunotherapy of GBM and other solid tumors.

Several studies have shown that female reproductive factors are associated with breast cancer (BC), but the results differ. We conducted two-sample MR in the present work. The raw data applied in the MR study were all from the Genome-wide association study (GWAS) database. The causal effect of reproductive factors on breast cancer were mainly estimated by the standard inverse variance weighted (IVW) method. Cochran’s Q test and I² statistics were used to assess heterogeneity. The pleiotropy was evaluated by MR-Egger intercept test and MR-PRESSO. Finally, the leave-one-out analysis was performed to evaluate the robustness of the MR results. We found that there was a negative causal effect of the age at last live birth on BC (OR = 0.687, 95%CI = 0.539–0.875, p = 0.002) and positive effect of the age at menopause on BC (OR = 1.054, 95%CI = 1.034–1.075, p = 8.010 × 10⁻⁸). Additionally, there were null effects of the age at menarche (OR = 0.977, 95%CI = 0.915–1.043, p = 0.484), the age at first sexual intercourse (OR = 1.053, 95%CI = 0.958–1.157, p = 0.284) and the age at first birth (OR = 0.981, 95%CI = 0.936–1.027, p = 0.404) on BC. All these results were reliable and stable. In conclusion, the present study showed that younger age at last birth and older age at menopause could increase the risk of BC.