Copy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis

Chen, Yiyu; Ge, Jing-Yu; Zhu, Siyuan; Shao, Zhi‐Ming; Yu, Ke-Da

doi:10.1038/s41467-022-28452-z

Cited by 37 publications

(17 citation statements)

References 65 publications

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“…This patient progressed within 7 months on trastuzumab, emphasising the need for regular re-evaluating tumour characteristics during the course of the disease, as is shown possible with liquid biopsies. Moreover, various additional amplifications were seen in 1q, 5q, 12, and 16p, in part of the CTC and DTC samples of patient 3, stressing the aggressive nature, possibly even subtype switch, of the metastatic disease in this patient that was ER+ on primary tumour biopsy (51), as chromosome 1q and 12p amplifications are associated with TNBC/basal-like breast cancer and poor survival (54,55). These co-occurring alterations, absent in the primary tumour, were initially predominantly present in the bone marrow, then emerging in the cerebrospinal fluid, to only become dominant in the CTC compartment after second progression.…”

Section: Discussionmentioning

confidence: 91%

Mutational and copy number analysis of numerous sorted circulating and disseminated tumour cells to interrogate subclonal evolution in advanced breast cancer.

Brouwer

Laere

Dam

et al. 2023

Preprint

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Background. Liquid biopsies have been studied as an accessible method to capture spatial tumour heterogeneity and repeatedly evaluate targetable aberrations in cancer. Here, we analysed pure single and pools of circulating and disseminated tumour cells (CTC and DTC) to study genetic heterogeneity. Methods. From, three patients with metastatic breast cancer, CTC and DTC (bone marrow, pleural fluid, and cerebrospinal fluid) were CellSearch® enriched and DEPArray® sorted into 136 samples of singles and pools up to 150 cells. Sorted cells, primary tumour, circulating free (cf)DNA, and enriched CTC/DTC fractions were analysed for mutations and copy number alterations (CNA). Results. Two patients harboured a driver PIK3CA mutation in all samples. Variant allele frequencies matched the ploidy status calculated from copy number data. The majority of CNA were homogeneously present in most samples of each patient, including breast cancer subtype specific CNA. One patient with rapidly progressive disease harboured additional CNA in the CTC/DTC compartment, reflecting this aggressive course and a possible subtype switch. These clones emerged at distinct timepoints in the different compartments. Furthermore, various mutations were present in unique samples. Conclusion. Repeated tumour analysis with liquid biopsies unveils changing molecular characteristics over time, and even a difference between simultaneous primary and metastatic disease. We show that all major subclones can be captured by combined sequencing of enriched CTC and cfDNA at disease progression.

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Section: Discussionmentioning

confidence: 91%

Mutational and copy number analysis of numerous sorted circulating and disseminated tumour cells to interrogate subclonal evolution in advanced breast cancer.

Brouwer

Laere

Dam

et al. 2023

Preprint

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“…(Figure 4f). The abnormal cholesterol metabolism is reported to be closely related to the occurrence of a wide variety of tumor development (Chen et al., 2022). And a number of clinical and preclinical studies demonstrated that intervening the cholesterol metabolism in tumor cells and immune cells has been proved to be an effective treatment against cancer.…”

Section: Resultsmentioning

confidence: 99%

Identification of a 2‐phenylthiazole derivative acetylcholinesterase modulator with in vitro antitumor activity in breast cancer cells

Shi,

Liu,

et al. 2023

Chem Biol Drug Des

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Acetylcholinesterase (AchE) is a serine hydrolase with classical function to degrade acetylcholine and terminate neurotransmission. While “nonclassical” functions of AchE were involved in cell growth, death, invasion, etc. The expression and activity of AchE is changed in tumors, suggesting AChE inhibitors (AchEIs) may serve as potential antitumor drugs. In this study, the antitumor activity of a series of 2‐phenylthiazole derivatives originally designed and synthesized as AchEIs were investigated. One compound named A6, was screened out with superior antitumor efficacy, especially against breast cancer MCF‐7 cells. A6 significantly disrupted the amino acid metabolism and inhibited migration of MCF‐7. In addition, A6 induced apoptosis of MCF‐7 cells. To clarify how A6 affected on MCF‐7 cells, RNA‐seq analysis was conducted to evaluate the whole genome effect of A6 on gene expression. A total of 153 genes were increased, and the expression of 81 genes was decreased. GO and KEGG enrichment analysis showed A6 treatment mainly disrupted sterol/cholesterol pathway, Ras signaling pathway, VEGF signaling pathway, etc. Moreover, bioinformatic analysis and cell viability test showed A6 plays anticancer role by regulating Best1 and HIST1H2BJ. These results indicate that AchEI A6 could be a potential antitumor agent for breast cancer patients and could help the development of novel therapies.

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“…Since somatic copy number alteration (SCNA) detection tools are prone to high false positive rates as well as issues with precision and accuracy ( 59 , 60 ), we also performed SCNA calling using CNVkit ( 61 ), which combines all normal samples into a pooled reference to increase performance. In contrast to Sequenza, this method identified a greater number of SCNA in primary TNBC relative to BrM, showing that, as a collective group, primary TNBC samples harbored 27 significant amplicons and 17 deleted regions, whereas BrM had 8 significant amplicons and 4 regions of deletion ( q < 0.25; Figures 1E, F ) .…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419

et al. 2022

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BackgroundTriple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease.MethodsWhole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC—Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed.ResultsPrimary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM.ConclusionsBrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted.

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Copy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis

Cited by 37 publications

References 65 publications

Mutational and copy number analysis of numerous sorted circulating and disseminated tumour cells to interrogate subclonal evolution in advanced breast cancer.

Mutational and copy number analysis of numerous sorted circulating and disseminated tumour cells to interrogate subclonal evolution in advanced breast cancer.

Identification of a 2‐phenylthiazole derivative acetylcholinesterase modulator with in vitro antitumor activity in breast cancer cells

Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419

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