In vivo modeling of the EGFR family in breast cancer progression and therapeutic approaches

Simond, Alexandra M.; Muller, William J.

doi:10.1016/bs.acr.2020.04.004

Cited by 9 publications

(7 citation statements)

References 173 publications

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“…The EGFR signalling pathway is a central driver of tumourigenesis and a major drug target in various solid malignancies, including lung, breast, colon and bladder tumours. 43 , 44 , 45 , 46 , 47 , 48 , 49 Aberrant activation and expression of EGFR have been frequently reported in BC. 50 , 51 , 52 , 53 , 54 These promote the proliferation, motility and invasive capacity of BC cells.…”

Section: Discussionmentioning

confidence: 99%

METTL1‐m⁷G‐EGFR/EFEMP1 axis promotes the bladder cancer development

Ying

Liu

Yuan

et al. 2021

Clinical & Translational Med

110

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Background The posttranscriptional modifications of transfer RNA (tRNA) are critical for all aspects of the tRNA function and have been implicated in the tumourigenesis and progression of many human cancers. By contrast, the biological functions of methyltransferase‐like 1 (METTL1)‐regulated m 7 G tRNA modification in bladder cancer (BC) remain obscure. Results In this research, we show that METTL1 was highly expressed in BC, and its level was correlated with poor patient prognosis. Silencing METTL1 suppresses the proliferation, migration and invasion of BC cells in vitro and in vivo. Multi‐omics analysis reveals that METTL1‐mediated m 7 G tRNA modification altered expression of certain target genes, including EGFR/EFEMP1. Mechanistically, METTL1 regulates the translation of EGFR/EFEMP1 via modifying certain tRNAs. Furthermore, forced expression of EGFR/EFEMP1 partially rescues the effect of METTL1 deletion on BC cells. Conclusions Our findings demonstrate the oncogenic role of METTL1 and the pathological significance of the METTL1‐m 7 G‐EGFR/EFEMP1 axis in the BC development, thus providing potential therapeutic targets for the BC treatment.

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Section: Discussionmentioning

confidence: 99%

METTL1‐m⁷G‐EGFR/EFEMP1 axis promotes the bladder cancer development

Ying

Liu

Yuan

et al. 2021

Clinical & Translational Med

110

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“…Most of previous studies using mouse models of HER2+ breast cancer focused on addressing the processes that took place in tumors rather than in mammary ducts prior to tumor formation 19,20 . Thus, we sought to characterize the Neu overexpression-induced cellular and molecular changes in pre-cancerous mammary ducts.…”

Section: Neu Overexpression Results In Ductal Ectasia In Mammary Glan...mentioning

confidence: 99%

HER2 overexpression initiates breast tumorigenesis non-cell-autonomously by inducing oxidative stress in the tissue microenvironment

Gurler,

Wagstaff,

Dimitrova

et al. 2023

Preprint

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SUMMARYHER2 is considered as a driver oncogene responsible for the HER2+ subtype of breast cancer. However, it is still unclear how HER2 induces the oncogenic transformation of breast cancer stem cells (BCSCs) and initiates tumorigenesis during premalignant stage breast cancer. Here, we used clinical samples and mouse models of HER2+ breast cancer to demonstrate that neither BCSCs nor their cell-of-origin express HER2/Neu in early-stage breast tumors. Instead, our results demonstrate that Neu overexpression results in the transformation of BCSCs in a non-cell-autonomous manner via triggering DNA damage and somatic mutagenesis in their Neu-negative cell-of-origin. This is caused by the increased oxidative stress in the tissue microenvironment generated by altered energy metabolism and increased reactive oxygen species levels in Neu-overexpressing mammary ducts. Therefore, our findings illustrate a previously unrecognized mechanism of HER2-induced breast tumor initiationin vivowith potential impacts on future preventive treatments for HER2+ premalignant breast cancer.

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“…Using two well-defined genetically engineered mouse models of BC driven by the PyMT and Her2 oncogenes, respectively, we directly probed the importance of the INSR to the development of mammary tumours by its coordinate genetic deletion in tumour tissue. Transcriptional profiling classifies PyMT mammary tumors with the human BC luminal B subtype 42 , whereas mammary tumours in the Her2 transgene model recapitulate many of the features of Her2-positive human BCs 43 . Control tumours from both models express INSR ( Figures 2F-G ), a feature found in >80% of human BC 17,18 .…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistically, mammary tumours driven by PyMT result from association-dependent activation of RTK-proximal effectors of mitogenic PI3K-Akt and Ras-MAPK signaling pathways 63,64 and the same pathways are also activated by superphysiological transgenesis of HER2 62 . From the tumour analysis at endpoint, INSR loss did not affect measures of proliferation, nor the PI3K-Akt and Ras-MAPK signaling throughput, highly representative of a tumour’s stage of progression rather than INSR deficiency ( Figure 4; Supplementary Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

Insulin Receptor Loss Impairs Mammary Tumorigenesis in Mice

Podmore

Poloz

Mouaaz

et al. 2022

Preprint

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Breast cancer (BC) prognosis and outcome are adversely affected by increased body weight, obesity and the obesity-associated type 2 diabetes. Hyperinsulinemia, which is commonly seen as part of metabolic reprograming in the obese state, has been associated with higher risk of death and recurrence in BC. Up to 80% of breast cancers overexpress the insulin receptor (INSR) de novo, which correlates with worse prognosis. To directly probe the role of insulin signaling in mammary tumorigenesis in the mouse, we generated the MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC models, respectively, with coordinate mammary epithelium-restricted deletion of the INSR. In both models, deletion of either one or both copies of the INSR in the mammary gland led to a marked delay in tumor onset and burden, including in mice fed to mimic conditions of human obesity. Longitudinal monitoring of generated mouse models revealed that tumor initiation, rather than progression and metastasis, were impacted by INSR deletion. The similarity of phenotypes elicited by the deletion of one or both copies of INSR raises the possibility that there is a dose-dependent threshold for the contribution of INSR to mammary tumorigenesis.

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In vivo modeling of the EGFR family in breast cancer progression and therapeutic approaches

Cited by 9 publications

References 173 publications

METTL1‐m⁷G‐EGFR/EFEMP1 axis promotes the bladder cancer development

METTL1‐m⁷G‐EGFR/EFEMP1 axis promotes the bladder cancer development

HER2 overexpression initiates breast tumorigenesis non-cell-autonomously by inducing oxidative stress in the tissue microenvironment

Insulin Receptor Loss Impairs Mammary Tumorigenesis in Mice

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In vivo modeling of the EGFR family in breast cancer progression and therapeutic approaches

Cited by 9 publications

References 173 publications

METTL1‐m7G‐EGFR/EFEMP1 axis promotes the bladder cancer development

METTL1‐m7G‐EGFR/EFEMP1 axis promotes the bladder cancer development

HER2 overexpression initiates breast tumorigenesis non-cell-autonomously by inducing oxidative stress in the tissue microenvironment

Insulin Receptor Loss Impairs Mammary Tumorigenesis in Mice

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Product

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METTL1‐m⁷G‐EGFR/EFEMP1 axis promotes the bladder cancer development

METTL1‐m⁷G‐EGFR/EFEMP1 axis promotes the bladder cancer development