Metabolome Sequencing Reveals that Protein Arginine-N-Methyltransferase 1 Promotes the Progression of Invasive Micropapillary Carcinoma of the Breast and Predicts a Poor Prognosis.

Invasive micropapillary carcinoma (IMPC) of the breast is a special histopathologic type of cancer with a high recurrence rate and the biological features of invasion and metastasis. Previous spatial transcriptome studies indicated extensive metabolic reprogramming in IMPC, which contributes to tumor cell heterogeneity. However, the impact of metabolome alterations on IMPC biological behavior is unclear. Herein, endogenous metabolite-targeted metabolomic analysis was done on frozen tumor tissue samples from 25 patients with breast IMPC and 34 patients with invasive ductal carcinoma not otherwise specified (IDC-NOS) by liquid chromatography-mass spectrometry. An IMPC-like state, which is an intermediate transitional morphologic phenotype between IMPC and IDC-NOS, was observed. The metabolic type of IMPC and IDC-NOS was related to breast cancer molecular type. Arginine methylation modification and 4-hydroxy-phenylpyruvate metabolic changes play a major role in the metabolic reprogramming of IMPC. High protein arginine-N-methyltransferase (PRMT) 1 expression was an independent factor related to the poor prognosis of patients with IMPC in terms of disease-free survival. PRMT1 promoted H4R3me2a, which induced tumor cell proliferation via cell cycle regulation and facilitated tumor cell metastasis via the tumor necrosis factor signaling pathway. This study identified the metabolic type-related features and intermediate transition morphology of IMPC. The identification of potential targets of PRMT1 has the potential to provide a basis for the precise diagnosis and treatment of breast IMPC.

Diagnostic value of alkaline phosphatase and bone-specific alkaline phosphatase for metastases in breast cancer: a systematic review and meta-analysis.

PURPOSE: Numerous studies had reported the diagnostic value of alkaline phosphatase (ALP) and its bone-specific isoforms (BAP) in the metastases of breast cancer (BC). The purpose of this meta-analysis was to summarize the diagnostic value of serum ALP and BAP in metastatic BC, especially focused on bone metastases. METHODS: We searched comprehensively in the PubMed, Cochrane Library, and EMBASE for studies to explore the diagnostic accuracy of serum ALP/BAP level for metastatic BC. Qualities of including studies were assessed and pooled sensitivity, specificity, and summary receiver operating characteristic curve were calculated. Publication bias was assessed and meta-regression was conducted. RESULTS: We finally included 25 studies with a total of 12,155 BC patients (1681 metastatic cases and 10,474 controls). According to the QUADAS-2 tool to assessment the methodological quality, most of the included studies were judged as high risk of patient selection bias. High serum levels of ALP/BAP in bone metastatic BC patients could be found compared with non-metastatic BC patients. The pooled sensitivity and specificity of ALP for BC bone metastases were 0.62 and 0.86, and the area under the curve (AUC) was 0.80. The pooled sensitivity and specificity of ALP for all site metastases (mainly bone and liver) were 0.56 and 0.91, and the AUC was 0.90. The pooled sensitivity and specificity of BAP for BC bone metastases were 0.66 and 0.92, and the AUC was 0.89. CONCLUSION: Although not promising, serum ALP and BAP could bring useful information for the early detection of BC metastases especially for the bone metastases.

STAT3 and PD-L1 are negatively correlated with ATM and have impact on the prognosis of triple-negative breast cancer patients with low ATM expression.

INTRODUCTION: Triple-negative breast cancer (TNBC) is known for its aggressive behaviors and lacking of effective treatment. Programmed cell death ligand-1 (PD-L1) inhibitor has just been approved for using in the management of advanced TNBC. To accurately screen TNBC sensitive to anti-PD-L1 treatment and to explore the feasibility of the ataxia-telangiectasia mutation protein (ATM) inhibitor combined with PD-L1 inhibitor, radiotherapy and chemotherapy, we focus on whether ATM participates in the regulation of PD-L1 and affects the prognosis of patients through c-Src, signal transducer and activator of transcription 1&3 (STAT1 and STAT3). MATERIALS AND METHODS: We used immunohistochemical staining to explore the relationship of ATM with c-Src, STAT1, STAT3, PD-1/PD-L1, Tumor-infiltrating lymphocytes (TILs), as well as other clinicopathologic features in 86 pathological stage III TNBCs. Their impact on prognosis was also explored. RESULTS: We found ATM expression was negatively correlated with STAT1, STAT3, PD-L1, TILs and CD8 + cells in TNBC. STAT1 positively correlated the expression of PD-L1. In TNBC with ATM low expression, STAT3 was an independent factor for improved prognosis, while PD-L1 was an independent negative prognostic factor. Furthermore, in low ATM group, the phosphorylation of tyrosine at position 419 of c-Src (p-c-src Y419) was correlated with the overexpression of STAT3. CONCLUSION: Locally advanced TNBC with low ATM expression may be more likely to benefit from anti-PD-L1 inhibitors. The feasibility of ATM functional inhibitor combined with immune checkpoint blockade therapies in the treatment of TNBC is also worthy of further exploration. Our study suggests that STAT3 has different impacts on tumor progression in different tumors.

Inhibition of ATM promotes PD-L1 expression by activating JNK/c-Jun/TNF-α signaling axis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer. Anti-PD-1/PD-L1 treatment for advanced TNBC is still limited to PD-L1-positive patients. Ataxia telangiectasia mutated (ATM) is a switch molecule for homologous recombination and repair. In this study, we found a significant negative correlation between ATM and PD-L1 in 4 TNBC clinical specimens by single-cell RNA sequencing (scRNA-seq), which was confirmed by immunochemical staining in 86 TNBC specimens. We then established ATM knockdown TNBC stable cell lines to perform in vitro studies and animal experiments, proving the negative regulation of PD-L1 by ATM via suppression of tumor necrosis factor-alpha (TNF-α), which was confirmed by cytokine array analysis of TNBC cell line and analysis of clinical specimens. We further found that ATM inhibits TNF-α via inactivating JNK/c-Jun by scRNA-seq, Western blot and luciferase reporter assays. Finally, we identified a negative correlation between changes in phospho-ATMS1981 and PD-L1 levels in TNBC post- and pre-neoadjuvant therapy. This study reveals a novel mechanism by which ATM negatively regulates PD-L1 by downregulating JNK/c-Jun/TNF-α in TNBC, shedding light on the wide application of immune checkpoint blockade therapy for treating multi-line-resistant TNBC.

Spatial transcriptomics reveals gene expression characteristics in invasive micropapillary carcinoma of the breast.

Invasive micropapillary carcinoma (IMPC) is a special histological subtype of breast cancer, featured with extremely high rates of lymphovascular invasion and lymph node metastasis. Based on a previous series of studies, our team proposed the hypothesis of "clustered metastasis of IMPC tumor cells". However, the transcriptomics characteristics underlying its metastasis are unknown, especially in spatial transcriptomics (ST). In this paper, we perform ST sequencing on four freshly frozen IMPC samples. We draw the transcriptomic maps of IMPC for the first time and reveal its extensive heterogeneity, associated with metabolic reprogramming. We also find that IMPC subpopulations with abnormal metabolism are arranged in different spatial areas, and higher levels of lipid metabolism are observed in all IMPC hierarchical clusters. Moreover, we find that the stromal regions show varieties of gene expression programs, and this difference depends on their distance from IMPC regions. Furthermore, a total of seven IMPC hierarchical clusters of four samples share a common higher expression level of the SREBF1 gene. Immunohistochemistry results further show that high SREBF1 protein expression is associated with lymph node metastasis and poor survival in IMPC patients. Together, these findings provide a valuable resource for exploring the inter- and intra-tumoral heterogeneity of IMPC and identify a new marker, SREBF1, which may facilitate accurate diagnosis and treatment of this disease.