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Abstract The mitochondrial calcium uniporter (MCU) is a transmembrane protein facilitating the entry of calcium ions into mitochondria from the cell cytosol. Maintaining calcium balance is crucial for enhancing cellular energy supply and regulating cell death. The interplay of calcium balance through MCU and the sodium-calcium exchanger is known, but its regulation in the breast cancer tumor microenvironment remains elusive. Further investigations are warranted to explore MCU’s potential in BRCA clinical pathology, tumor immune microenvironment, and precision oncology. Our study, employing a multi-omics approach, identifies MCU as an independent diagnostic biomarker for breast cancer (BRCA), correlated with advanced clinical status and poor overall survival. Utilizing public datasets from GEO and TCGA, we discern differentially expressed genes in BRCA and examine their associations with immune gene expression, overall survival, tumor stage, gene mutation status, and infiltrating immune cells. Spatial transcriptomics is employed to investigate MCU gene expression in various regions of BRCA, while spatial transcriptomics and single-cell RNA-sequencing methods explore the correlation between MCUs and immune cells. Our findings are validated through the analysis of 59 BRCA patient samples, utilizing immunohistochemistry and bioinformatics to examine the relationship between MCU expression, clinicopathological features, and prognosis. The study uncovers the expression of key gene regulators in BRCA associated with genetic variations, deletions, and the tumor microenvironment. Mutations in these regulators positively correlate with different immune cells in six immune datasets, playing a pivotal role in immune cell infiltration in BRCA. Notably, high MCU performance is linked to CD8 + T cells infiltration in BRCA. Furthermore, pharmacogenomic analysis of BRCA cell lines indicates that MCU inactivation is associated with increased sensitivity to specific small molecule drugs. Our findings suggest that MCU alterations may be linked to BRCA progression, unveiling new diagnostic and prognostic implications for MCU in BRCA. The study underscores MCU's role in the tumor immune microenvironment and cell cycle progression, positioning it as a potential tool for BRCA precision medicine and drug screening.

LSM1 is part of the cytoplasmic protein complex Lsm1–7-Pat1 and is likely involved in pre-mRNA degradation by aiding U4/U6 snRNP formation. More research is needed to uncover LSM1's potential in breast cancer (BRCA) clinical pathology, the tumor immune microenvironment, and precision oncology. We discovered LSM1 as a diagnostic marker for advanced BRCA with poor survival, using a multi-omics approach. We studied LSM1 expression across BRCA regions and its link to immune cells through various methods, including spatial transcriptomics and single-cell RNA-sequencing. We also examined how silencing LSM1 affects mitochondrial function and energy metabolism in the tumor environment. These findings were confirmed using 54 BRCA patient biopsies and tissue microarrays. Immunofluorescence and bioinformatics assessed LSM1's connection to clinicopathological features and prognosis. This study uncovers gene patterns linked to breast cancer, with LSM1 linked to macrophage energy processes. Silencing LSM1 in breast cancer cells disrupts mitochondria and energy metabolism. Spatial analysis aligns with previous results, showing LSM1's connection to macrophages. Biopsies confirm LSM1 elevation in advanced breast cancer with increased macrophage presence. To summarize, LSM1 changes may drive BRCA progression, making it a potential diagnostic and prognostic marker. It also influences energy metabolism and the tumor's immune environment during metastasis, showing promise for precision medicine and drug screening in BRCA.

Breast cancer is the leading cause of cancer death in women worldwide. The microtubule-associated protein light chain 3B (MAP1LC3B) and adaptor sequestosome 1 (SQSTM1) are two major markers for autophagy. Increased protein levels of MAP1LC3B and SQSTM1 are considered to be causes of autophagy inhibition or activation in various types of cancers. However, the roles of MAP1LC3B and SQSTM1 in breast cancer are still not clear. Using a tissue microarray from 274 breast invasive ductal carcinoma (IDC) patients, we found that tumor tissues showed higher protein levels of MAP1LC3B and cytoplasmic SQSTM1 in comparison to those in adjacent normal tissues. Moreover, high levels of MAP1LC3B were associated with better survival, including disease-specific survival and disease-free survival (DFS) in IDC patients. Furthermore, high co-expression of MAP1LC3B and SQSTM1 was significantly associated with better DFS in IDC patients. Astonishingly, the autophagy inhibitor accumulated the protein levels of MAP1LC3B/SQSTM1 and enhanced the cytotoxic effects of cisplatin and paclitaxel in MCF7 and BT474 breast cancer cell lines, implying that autophagy inhibition might result in poor prognosis and chemosensitivity in IDC. Taken together, high co-expression of MAP1LC3B and SQSTM1 might serve as a potential diagnostic and prognostic biomarker for IDC patients.

Utilization of circulating tumor DNA as a novel and noninvasive test for diagnosis confirmation, therapy selection, and cancer surveillance is a rapidly growing area of interest. In the wake of FDA approval of a liquid biopsy test, it is important for clinicians to acknowledge the obvious clinical utility of liquid biopsy for cancer management throughout the course of the disease. This case report describes a female with invasive ductal adenocarcinoma of the breast, where liquid biopsy was instrumental for her cancer characterization and personalized therapy selection.

E3 ubiquitin-linked enzyme MARCH5, also known as membrane-associated circular finger 5, is an enzyme encoded by the human MARCH5 gene. The main objective of this study was to visualize the prognosis of MARCH5 in breast cancer and to determine the relationship between MARCH5 expression and tumor immunity. MARCH5 expression was significantly higher in several cancers, including breast cancer (BRCA), compared with corresponding normal tissues. Not only was high MARCH5 expression associated with poorer overall survival, but also MARCH5 expression was positively correlated with the number of tumor-infiltrating immune cells in BRCA malignant tissues. Furthermore, MARCH5 expression showed a strong correlation with various immune markers of BRCA, suggesting its role in regulating tumor immunity. MARCH5 is a useful prognostic biomarker in several cancers, and its expression is highly correlated with tumor immune cell infiltration, and increased MARCH5 expression may serve as a new biomarker for BRCA diagnosis and prognosis.

Background: Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), which lack molecular markers for diagnosis and therapy. Cancer cells activate chemoresistant pathways and lead to therapeutic failure for patients with TNBC. Several kinases have been identified as chemoresistant genes. However, the involvement of kinases in the chemoresistance in TNBC cells is not fully understood.Methods: We employed a kinome siRNA library to screen whether targeting any kinases could increase the chemosensitivity of TNBC cell lines. The effects of kinase on cell viability in various breast cancer cells were validated with ATP level and colony formation. Protein expression and phosphorylation were determined by immunoblotting. The Cancer Genome Atlas (TCGA) dataset was collected to analyze the correlation of Src expression with prognosis of TNBC patients.Results: Primary screening and validation for the initial hits showed that Src kinase was a potential doxorubicin-resistant kinase in the TNBC cell lines MDA-MB-231 and Hs578T. Both siRNA against Src and the Src inhibitor dasatinib enhanced the cytotoxic effects of doxorubicin in TNBC cells. Moreover, phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), downstream effectors of Src, were accordingly decreased in Src-silenced or -inhibited TNBC cells. Additionally, TCGA data analysis indicated that Src expression levels in tumor tissues were higher than those in tumor-adjacent normal tissues in patients with TNBC. High co-expression level of Src and STAT3 was also significantly correlated with poor prognosis in patients.Conclusion: Our results showed that Src-STAT3 axis might be involved in chemoresistance of TNBC cells.

Acquired resistance to aromatase inhibitors (AIs) is a significant clinical issue in endocrine therapy for estrogen receptor (ER) positive breast cancer which accounts for the majority of breast cancer. Despite estrogen production being suppressed, ERa signaling remains active and plays a key role in most AI-resistant breast tumors. Here, we found that amphiregulin (AREG), an ERa transcriptional target and EGF receptor (EGFR) ligand, is crucial for maintaining ERa expression and signaling in acquired AI-resistant breast cancer cells. AREG was deregulated and critical for cell viability in ER+ AI-resistant breast cancer cells, and ectopic expression of AREG in hormone responsive breast cancer cells promoted endocrine resistance. RNA-sequencing and reverse phase protein array analyses revealed that AREG maintains ERa expression and signaling by activation of PI3K/Akt/mTOR signaling and upregulation of forkhead box M1 (FOXM1) and serum- and glucocorticoid-inducible kinase 3 (SGK3) expression. Our study uncovers a previously unappreciated role of AREG in maintaining ERa expression and signaling, and establishes the AREG-ERa crosstalk as a driver of acquired AI resistance in breast canc er. [ABSTRACT FROM AUTHOR]