The findings regarding the association between statins use and breast cancer are inconsistent. Given the widely and long-term use of statins as first choice drug for dyslipidemia, we conducted this meta-analysis for better understanding the associations between statins use and the risk and prognosis of breast cancer. Articles regarding effect of statins use on risk, prognosis of breast cancer and published before January 2021 were searched in the following databases: Web of Science, PubMed, EMBASE, Medline and Google Scholar. Odds ratios (ORs)/ relative risks (RRs) or hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed to generate a pooled effect size and 95% CI. The meta-analysis showed no significant association between statins use and risk of breast cancer (OR/RR = 1.02; 95% CI, 0.97-1.08; I 2 = 76.1%; P < 0.001). The meta-analysis showed that statins use was associated with lower breast cancer recurrence, all-cause mortality and disease-specific mortality (breast cancer recurrence: HR = 0.75; 95% CI, 0.67-0.84; I 2 = 31.7%; P = 0.154; all-cause mortality: HR = 0.82; 95% CI, 0.77-0.89; I 2 = 67.5%; P < 0.001; and disease-specific mortality: HR = 0.82; 95% CI, 0.72-0.93; I 2 = 83.6%; P < 0.001). Overall, in this report we demonstrated that the use of statins can improve the prognosis of breast cancer patients including lower risks of breast cancer recurrence, all-cause and cancer-specific mortality, though statins therapy may not have an impact on reducing the risk of breast cancer. Anti-Cancer Drugs 33: e507-e518
Breast cancer is the most prevalent tumour in women. Over two-thirds of breast cancers are estrogen receptor (ER)-positive breast cancers. These breast cancer patients are prone to tamoxifen resistance during breast cancer treatment. There is still a lack of effective clinical treatment for tamoxifen-resistant breast cancer. Dihydrotanshinone I (DHTS) promotes various types of apoptosis in tumour cells. Our network pharmacology study revealed that DHTS has a strong binding capacity to STAT3. Tamoxifen-resistant breast cancers are often accompanied by STAT3 activation. However, there are no reports of DHTS for tamoxifen-resistant breast cancer. Subsequent in vitro experiments also confirmed that DHTS promoted apoptosis in MCF-7-TamR cells, down-regulated the performance of STAT3, pSTAT3, and BCL-2, and activated the production of apoptosisassociated PARP1 and cleaved caspase3. This process could be rescued by overexpression of BCL-2 downstream of STAT3 and was not rescued by either the cytokine EGF or the cytokine PDGF, which promote STAT3 phosphorylation. We hypothesized that DHTS targeting STAT3 promotes apoptosis in MCF-7-TamR cells, mainly by affecting STAT3 phosphorylation. Our research approach described above may provide new ideas for the treatment of tamoxifen-resistant breast cancer.
Background: Transmembrane p24 trafficking protein (TMED) family members are implicated in several solid tumors, but their clinical relevance for breast cancer (BC) remains unclear. This study aimed to probe their prognostic values and relations with tumor immunity in BC.Methods: TMED family mRNA expression was assessed in five microarray datasets (GSE65212, GSE42568, GSE5364, GSE22820 and GSE45827) from Gene Expression Omnibus (GEO) database and invasive breast cancer (BRCA) cohort from The Cancer Genome Atlas (TCGA). Receiver operating characteristic (ROC) curve was performed to determine the predictive values of filtered members of the TMED family. The protein expressions of screen genes were validated by Clinical Proteomic Tumor Analysis Consortium (CPTAC) data from University of ALabama at Birmingham CANcer data analysis portal (UALCAN) and detected in the clinical specimens by western blot assay. Clinicopathologic variables were analyzed with bc-GenExMiner, and patient prognostic data were obtained with Kaplan-Meier Plotter.In vitro wound healing and invasion assays were performed on siRNA-transfected BC cell lines. TIMER 2.0, SangerBox, and ImmPort were used to evaluate tumor immune infiltration, immune checkpoints, and other immune-related genes. CbioPortal, Metascape, Expression2kinases, and LinkedOmics were used to explore gene regulatory network.Results: BC tissues expressed TMED2/3/4/9 at a higher level than normal tissues, providing diagnostic potential. All the areas under the ROC curve for TMED2/3/4/9 were more than 0.7. TMED2/3/4/9 correlated with numerous clinical variables, including lymph node status, Scarff-Bloom-Richardson score (SBR), Nottingham Prognostic Index (NPI), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and triple-negative breast cancer (TNBC) status, and their high expression predicted the poor prognosis of BC patients. TMED2/3/4/9 knockdown drastically inhibited the migratory and invasive capacities of MDA-MB-231 and HCC1937 cells. TMED2/3/4/9 expressions correlated negatively with the infiltration of tumor-suppressive immune cells such as CD8 + T cells, dendritic cells, and natural killer cells, and was inversely related to a variety of immune checkpoint genes, including programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4). A set of kinases, transcription factors, and microRNAs (miRNAs) may regulate TMED2/3/4/9 abnormalities at the genome level.
Background Leucine-rich repeat containing 15 (LRRC15), belongs to the LRR superfamily and has emerged as a marker of cancer-associated fibroblasts. It was found to be particularly upregulated in breast cancer (BCa). This study aimed to investigate the correlation between LRRC15 expression and immune microenviroment and visualize its prognostic landscape in BCa. Methods The mRNA expression level, prognostic value, correlation of immunity, gene-gene interaction network of LRRC15 in BCa were analyzed utilizing the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan-Meier plotter, and TIMER database. We next analyzed the biological functions of LRRC15 and pathways of its co-expressed genes, and its correlation with immune system responses via the Metascape and GeneMANIA database, respectively. We validated the expression of LRRC15 in BCa via western blot and IHC assays and analyzed its correlation with clinicopathological parameters. Results We explored LRRC15 expression in multiple types of cancer based on the Cancer Genome Atlas (TCGA) database, with the effect being particularly pronounced in BCa. Both mRNA and protein abundance of LRRC15 were significantly elevated in BCa as compared to its non-tumor counterparts. Overexpression of LRRC15 significantly associated with reduced overall survival. LRRC15 knockdown significantly inhibited cell proliferation and cell cycle in BCa cells. There were significant positive correlations between LRRC15 expression and tumor-infiltrating immune cells (TIICs), with a particularly strong effect on macrophage infiltration. Moreover, markers of TIICs exhibited different LRRC15-related immune infiltration patterns. GSEA analysis showed that upregulated expression of LRRC15 was related to ECM receptor interaction, focal adhesion, regulation of actin cytoskeleton, and TGF Beta signaling pathway. Conclusions These findings revealed that LRRC15 served as a novel prognostic biomarker and putative oncogene for BCa by promoting cell proliferation, giving a novel hint for therapeutics of BCa.
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