Altered Expression of Secreted Mediator Genes That Mediate Aggressive Breast Cancer Metastasis to Distant Organs

Maiti, Aparna; Okano, Ichiro; Oshi, Masanori; Okano, Maiko; Tian, Wanqing; Kawaguchi, Tsutomu; Katsuta, Eriko; Takabe, Kazuaki; Yan, Li; Patnaik, Santosh K.; Hait, Nitai C.

doi:10.3390/cancers13112641

Cited by 9 publications

(6 citation statements)

References 87 publications

(115 reference statements)

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“…We demonstrated that the expression of NR2F1 gene was higher in previously established dormant cells (D2OR murine breast cancer cells) [ 44 ] compared to the proliferative cells (D2A1 cells) in 3D cultures, and the expression of RARB and TGFB1 genes are higher in dormant cells compared to the proliferative cells in both 2D and 3D cultures ( Figure 1 A, all p < 0.02). Further, both NR2F1 and TGFB1 gene expressions were significantly higher in bone metastatic derivatives [ 45 ] compared with wild-type 4T1 murine breast cancer cells ( Figure 1 B). TGF-β signaling calculated by Thorsson et al [ 57 ] in the TCGA cohort was higher in the NR2F1 high group ( Figure 1 C).…”

Section: Resultsmentioning

confidence: 99%

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NR2F1, a Tumor Dormancy Marker, Is Expressed Predominantly in Cancer-Associated Fibroblasts and Is Associated with Suppressed Breast Cancer Cell Proliferation

Roy

Tokumaru

et al. 2022

Cancers

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Background: Tumor dormancy is a crucial mechanism responsible for the late recurrence of breast cancer. Thus, we investigated the clinical relevance of the expression of NR2F1, a known dormancy biomarker. Methods: A total of 6758 transcriptomes of bulk tumors from multiple breast cancer patient cohorts and two single-cell sequence cohorts were analyzed. Results: Breast cancer (BC) with high NR2F1 expression enriched TGFβ signaling, multiple metastases, and stem cell-related pathways. Cell proliferation-related gene sets were suppressed, and MKi67 expression was lower in high NR2F1 BC. In tumors with high Nottingham grade, NR2F1 expression was found to be lower. There was no consistent relationship between NR2F1 expression and metastasis or survival. Cancer mutation rates, immune responses, and immune cell infiltrations were lower in high NR2F1 tumors, whereas the infiltration of stromal cells including cancer-associated fibroblasts (CAFs) was higher. NR2F1 was predominantly expressed in CAFs, particularly inflammatory CAFs, rather than in cancer cells, consistently in the two single-cell sequence cohorts. Conclusions: NR2F1 expression in breast cancer is associated with tumor dormancy traits, and it is predominantly expressed in CAFs in the tumor microenvironment.

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Section: Resultsmentioning

confidence: 99%

“…The R package GEOquary was used to acquire and process data from GEO. We also used RNA-seq data of GSE172882 [ 44 ], a cohort of dormant D2.OR and proliferate D2A1 breast cancer cell lines, as well as 4T1 and metastasis-competent derivative cell line 4T1.2 from our previous publication [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

NR2F1, a Tumor Dormancy Marker, Is Expressed Predominantly in Cancer-Associated Fibroblasts and Is Associated with Suppressed Breast Cancer Cell Proliferation

Roy

Tokumaru

et al. 2022

Cancers

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“…Previous studies have found a correlation between LCN2 expression and disease aggression. For example, LCN2 has been positively associated with tumorigenesis, invasiveness, migration, metastasis [36][37][38][39] . Interestingly, LCN2 was included in several IPA cell movement gene signatures found to be The mechanism by which LCN2 may contribute to acquired EGFRi resistance requires further study, but it may be related to EGFR recycling.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic changes underlying EGFR inhibitor resistance in human and mouse models of basal-like breast cancer

Rashid

Boyd

Olex

et al. 2022

Sci Rep

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The goals of this study were to identify transcriptomic changes that arise in basal-like breast cancer cells during the development of resistance to epidermal growth factor receptor inhibitors (EGFRi) and to identify drugs that are cytotoxic once EGFRi resistance occurs. Human patient-derived xenografts (PDXs) were grown in immunodeficient mice and treated with a set of EGFRi; the EGFRi erlotinib was selected for more expansive in vivo studies. Single-cell RNA sequencing was performed on mammary tumors from the basal-like PDX WHIM2 that was treated with vehicle or erlotinib for 9 weeks. The PDX was then subjected to long-term erlotinib treatment in vivo. Through serial passaging, an erlotinib-resistant subline of WHIM2 was generated. Bulk RNA-sequencing was performed on parental and erlotinib-resistant tumors. In vitro high-throughput drug screening with > 500 clinically used compounds was performed on parental and erlotinib-resistant cells. Previously published bulk gene expression microarray data from MMTV-Wnt1 tumors were contrasted with the WHIM2 PDX data. Erlotinib effectively inhibited WHIM2 tumor growth for approximately 4 weeks. Compared to untreated cells, single-cell RNA sequencing revealed that a greater proportion of erlotinib-treated cells were in the G1 phase of the cell cycle. Comparison of WHIM2 and MMTV-Wnt1 gene expression data revealed a set of 38 overlapping genes that were differentially expressed in the erlotinib-resistant WHIM2 and MMTV-Wnt1 tumors. Comparison of all three data types revealed five genes that were upregulated across all erlotinib-resistant samples: IL19, KLK7, LCN2, SAA1, and SAA2. Of these five genes, LCN2 was most abundantly expressed in triple-negative breast cancers, and its knockdown restored erlotinib sensitivity in vitro. Despite transcriptomic differences, parental and erlotinib-resistant WHIM2 displayed similar responses to the majority of drugs assessed for cytotoxicity in vitro. This study identified transcriptomic changes arising in erlotinib-resistant basal-like breast cancer. These data could be used to identify a biomarker or develop a gene signature predictive of patient response to EGFRi. Future studies should explore the predictive capacity of these gene signatures as well as how LCN2 contributes to the development of EGFRi resistance.

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“…This method estimates the composition of 64 types of immune and stromal cells utilizing gene expression data of a bulk tumor. Utilizing this method, our group reported the clinical relevance of immune cells 36 – 39 , stromal cells 40 , 41 , and tumor immune microenvironment 42 – 54 in a number of settings in multiple types of cancer. The data for the current study was obtained through the webpage of xCell ( https://xcell.ucsf.edu/ ).…”

Section: Methodsmentioning

confidence: 99%

Low expression of miR-29a is associated with aggressive biology and worse survival in gastric cancer

Tokumaru

Oshi

Huyser

et al. 2021

Sci Rep

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Advanced gastric cancer (GC) is one of the most lethal cancer types, thus a better understanding of its biology in patients is urgently needed. MicroRNA (miR)-29a is a known tumor suppressive miR that is related to metastasis, but its clinical relevance in GC remains ambiguous. Here, using a large GC patient cohort we hypothesized that low expression of miR-29a in GC is associated with aggressive cancer biology and worse survival. We demonstrated that low miR-29a GC enriched cell proliferation, apoptosis, metastasis, and angiogenesis related gene sets, as well as the higher expression of related genes. Low miR-29a GC was associated with less anti-cancer immune cell infiltration as well as immune related scoring. Low miR-29a GC demonstrated a worse overall survival (OS) as well as disease specific survival (DSS) compared with high expressing miR-29a GC. Notably, low miR-29a expression was the only factor, other than residual tumor status, to be an independent prognostic biomarker of worse OS and DSS. In conclusion, low miR-29a GC was associated with aggressive cancer biology and worse OS as well as DSS. Additionally, low expression of miR-29a was an independent prognostic biomarker of OS and DSS in gastric cancer patients.

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Altered Expression of Secreted Mediator Genes That Mediate Aggressive Breast Cancer Metastasis to Distant Organs

Cited by 9 publications

References 87 publications

NR2F1, a Tumor Dormancy Marker, Is Expressed Predominantly in Cancer-Associated Fibroblasts and Is Associated with Suppressed Breast Cancer Cell Proliferation

NR2F1, a Tumor Dormancy Marker, Is Expressed Predominantly in Cancer-Associated Fibroblasts and Is Associated with Suppressed Breast Cancer Cell Proliferation

Transcriptomic changes underlying EGFR inhibitor resistance in human and mouse models of basal-like breast cancer

Low expression of miR-29a is associated with aggressive biology and worse survival in gastric cancer

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