Epithelial-mesenchymal transition and drug resistance in breast cancer (Review)

Huang, Jing; Li, Hongzhong; Ren, Guosheng

doi:10.3892/ijo.2015.3084

Cited by 126 publications

(93 citation statements)

References 100 publications

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“…EMT also contributes to drug resistance in advanced tumors (26). To understand the effect of microtumor size-induced EMT on drug response, 150 and 600 μm microtumors were treated with 4-OHT, a selective ER modulator.…”

Section: Resultsmentioning

confidence: 99%

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Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression

et al. 2016

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Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates (“microtumors”) of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150–600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes such as hypoxic gradients, cellular heterogeneity and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression.

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Section: Resultsmentioning

confidence: 99%

“…Advanced stage tumors often acquire drug resistance by EMT-mediated genetic changes (26). Hence, the drug response was studied by measuring cell growth in 150 and 600 μm microtumors after 50 μM 4-OHT treatment (Supplementary Information, Methods).…”

Section: Methodsmentioning

confidence: 99%

Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression

et al. 2016

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“…In fact, drugs that can block specific cancer cell dependent pathways such as: EGFR, BRAF, HER2, and HGF/c-Met signaling are being developed, and are predicted to have fewer side effects. Previous studies have shown that cells that undergo EMT are more resistant to cell death (109, 110), thus it is possible that the HGF-induced EMT is responsible for the increased resistance to therapy. In fact, in lung cancer cells with c-Met amplification, HGF has been shown to be responsible for the observed resistance to anti-MET treatment (111, 112).…”

Section: Hgf Signaling In Cancermentioning

confidence: 99%

The Role of Hepatocyte Growth Factor (HGF) in Insulin Resistance and Diabetes

et al. 2018

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In obesity, insulin resistance (IR) and diabetes, there are proteins and hormones that may lead to the discovery of promising biomarkers and treatments for these metabolic disorders. For example, these molecules may impair the insulin signaling pathway or provide protection against IR. Thus, identifying proteins that are upregulated in IR states is relevant to the diagnosis and treatment of the associated disorders. It is becoming clear that hepatocyte growth factor (HGF) is an important component of the pathophysiology of IR, with increased levels in most common IR conditions, including obesity. HGF has a role in the metabolic flux of glucose in different insulin sensitive cell types; plays a key role in β-cell homeostasis; and is capable of modulating the inflammatory response. In this review, we discuss how, and to what extent HGF contributes to IR and diabetes pathophysiology, as well as its role in cancer which is more prevalent in obesity and diabetes. Based on the current literature and knowledge, it is clear that HGF plays a central role in these metabolic disorders. Thus, HGF levels could be employed as a biomarker for disease status/progression, and HGF/c-Met signaling pathway modulators could effectively regulate IR and treat diabetes.

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“…Numerous studies have demonstrated that microRNAs (miRNAs) are involved in the process of epithelial-mesenchymal transition (EMT) in various types of cancer (3)(4)(5)(6), and various studies have revealed that the EMT may be associated with the drug resistance of cancer cells (7)(8)(9)(10). Furthermore, by comparing the miRNA expression profiles between breast cancer cell lines in our previous study, we determined that the expression of miR-93 was increased markedly in drug-resistant MCF-7/AdrVp cells compared with the parental MCF-7 cell line (11).…”

Section: Introductionmentioning

confidence: 99%

miR-93 and PTEN: Key regulators of doxorubicin-resistance and EMT in breast cancer

Chu

Xia

et al. 2017

Oncology Reports

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Abstract. It is not well established whether miR-93 is involved in drug resistance and epithelial-mesenchymal transition (EMT) in breast cancer, and its underlying mechanism remains uncertain. In the present study, the expression differences of miR-93 between paired breast cancer tissues confirmed it is involved in the progression of breast cancer. Such a difference was also observed in doxorubicin-resistant and -sensitive cells. Overexpressed miR-93 in sensitive cells revealed increases in cellular proliferation and the expression levels of drug-resistant-related genes, and a decrease in sensitivity to doxorubicin. This demonstrated the relationship between miR-93 and breast cancer drug resistance. Simultaneously, EMT was confirmed in miR-93 overexpressing sensitive cells. This indicated the triadic relationship among miR-93, EMT and drug resistance in breast cancer. We applied the Dual-luciferase Reporter assay to expose the direct interaction between miR-93 and PTEN, which suggested that miR-93 contributes to inducing EMT and drug resistance of breast cancer cells by targeting PTEN.

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Epithelial-mesenchymal transition and drug resistance in breast cancer (Review)

Cited by 126 publications

References 100 publications

Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression

Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression

The Role of Hepatocyte Growth Factor (HGF) in Insulin Resistance and Diabetes

miR-93 and PTEN: Key regulators of doxorubicin-resistance and EMT in breast cancer

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