Biomarkers for EMT and MET in breast cancer: An update

Liu, Fei; Gu, Lina; Shan, Baoen; Chen, Geng; Sang, Meixiang

doi:10.3892/ol.2016.5369

Cited by 104 publications

(82 citation statements)

References 97 publications

(99 reference statements)

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“…Furthermore, ten out of 11 pure spindle cases (WHO_5) assessed do not express E-cadherin, a finding consistent with the data of refs 30 and 31. The traditional, categorical dogma of an EMT, wherein vimentin switches on, while E-cadherin switches off [32], is not uniformly observed in these tumours, and indeed is likely to be different within the different morphological regions. It would be interesting to determine whether the transcriptional programme of EMT is also atypical in these tumours, as parallel studies of endometrial carcinosarcomas have identified differing miRNA programmes between the mesenchymal and epithelial components [33].…”

Section: Discussionmentioning

confidence: 91%

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Reed

Kalaw

Nones

et al. 2018

The Journal of Pathology

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Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5‐year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology – the biological basis and clinical relevance of its seven sub‐categories are currently unclear. By establishing the Asia‐Pacific MBC (AP‐MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan‐cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for ‘mixed’ MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis‐1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed‐type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan‐cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 91%

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Reed

Kalaw

Nones

et al. 2018

The Journal of Pathology

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“…We demonstrated that nWdl could inhibit EMT by triggering molecular reprogramming in MDA-MB-231 cells, with enhanced efficiency compared with wedelolactone. In addition, nWdl modulated "cadherin switching," by increasing the expression of E-cadherin and reducing the expression of N-cadherin (42,43). Snail and Slug, which are known to regulate expression of E-cadherin in TNBC cells (44), were also regulated by nWdl.…”

Section: Discussionmentioning

confidence: 99%

Enhancing Chemosensitivity of Breast Cancer Stem Cells by Downregulating SOX2 and ABCG2 Using Wedelolactone-encapsulated Nanoparticles

Das

Mukherjee

Chatterjee

et al. 2019

Molecular Cancer Therapeutics

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A major caveat in the treatment of breast cancer is disease recurrence after therapeutic regime at both local and distal sites. Tumor relapse is attributed to the persistence of chemoresistant cancer stem cells (CSC), which need to be obliterated along with conventional chemotherapy. Wedelolactone, a naturally occurring coumestan, demonstrates anticancer effects in different cancer cells, although with several limitations, and is mostly ineffective against CSCs. To enhance its biological activity in cancer cells and additionally target the CSCs, wedelolactone-encapsulated PLGA nanoparticles (nWdl) were formulated. Initial results indicated that nanoformulation of wedelolactone not only increased its uptake in breast cancer cells and the CSC population, it enhanced drug retention and sustained release within the cells. Enhanced drug retention was achieved by downregula-tion of SOX2 and ABCG2, both of which contribute to drug resistance of the CSCs. In addition, nWdl prevented epithelialto-mesenchymal transition, suppressed cell migration and invasion, and reduced the percentage of breast cancer stem cells (BCSC) in MDA-MB-231 cells. When administered in combination with paclitaxel, which is known to be ineffective against BCSCs, nWdl sensitized the cells to the effects of paclitaxel and reduced the percentage of ALDH þ BCSCs and mammospheres. Furthermore, nWdl suppressed growth of solid tumors in mice and also reduced CD44 þ /CD24 À/low population. Taken together, our data imply that nWdl decreased metastatic potential of BCSCs, enhanced chemosensitivity through coordinated regulation of pluripotent and efflux genes, and thereby provides an insight into effective drug delivery specifically for obliterating BCSCs.

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“…Metastasis is the spread of tumor cells from their origin of formation. It is a multistep phenomenon that is initiated by EMT (Liu et al, ). EMT occurs when epithelial cells lose their connections with their environment and achieve a mesenchymal phenotype, assisting them to enter blood circulation and migrate to distant locations (Bill & Christofori, ; Felipe Lima, Nofech‐Mozes, Bayani, & Bartlett, ).…”

Section: Emt In Breast Cancermentioning

confidence: 99%

“…Both EMT and the CSCs of a BC are associated with changes in gene expression (Rich, 2016;Smith & Bhowmick, 2016). It has been recently demonstrated that epigenetic phenomena and non-coding RNAs are master gene regulators of EMT and CSCs that overlaps the invasiveness of cancer cells (Liu, Gu, Shan, Geng, & Sang, 2016;Zaravinos, 2015).…”

mentioning

confidence: 99%

Aberrant miRNA promoter methylation and EMT‐involving miRNAs in breast cancer metastasis: Diagnosis and therapeutic implications

Zare

Bastami

Solali

et al. 2017

Journal Cellular Physiology

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Breast cancer (BC) is the most prevalent cancer in women worldwide. Although extensive studies are ongoing concerning its intricate molecular mechanisms, development of novel therapies and more accurate diagnostic and prognostic approaches is still a challenge. Epithelial-mesenchymal transition (EMT) enables the invasion of metastatic cancer cells and has recently been highlighted in a Cancer Stem Cell (CSC) model of BC. Epigenetic events as well as miRNA expression are the master regulators of tumorigenesis and add a further layer to the complexity of BC pathogenesis. The miRNAs are related to epigenetic event and additionally affect epigenetic pathways. Recent evidence demonstrates that epigenetic mechanisms such as DNA methylation may control miRNA expression. Because each miRNA may regulate several target genes, dysregulation of miRNA caused by aberrant DNA methylation patterns of the locus may influence important downstream pathways. Furthermore, some miRNAs is believed to regulate important DNA methylator factors. Any disruption or modification of this intricate network can contribute to the disease process; thus, it is essential to understand these changes. Advancements in new sequencing technologies to detect DNA methylation patterns has provided the opportunity to determine differentially methylated regions (DMRs) of the miRNA locus and their effect on expression profiles to improve BC diagnosis and treatment. The current review examines the interplay of DNA methylation mechanisms and miRNA function in invasive tumorigenesis, specifically EMT and CSC of BC, to highlight its potential for advancements on BC etiology, diagnosis, and therapy.

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Biomarkers for EMT and MET in breast cancer: An update

Cited by 104 publications

References 97 publications

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Enhancing Chemosensitivity of Breast Cancer Stem Cells by Downregulating SOX2 and ABCG2 Using Wedelolactone-encapsulated Nanoparticles

Aberrant miRNA promoter methylation and EMT‐involving miRNAs in breast cancer metastasis: Diagnosis and therapeutic implications

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