MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients

Mattos-Arruda, Leticia De; Bottai, Giulia; Nuciforo, Paolo; Tommaso, Luca Di; Giovannetti, Elisa; Peg, Vicente; Losurdo, Agnese; Peréz-García, José Manuel; Masci, Giovanna; Corsi, Fabio; Cortés, Javier; Seoane, Joan; Calin, George A.; Santarpia, Libero

doi:10.18632/oncotarget.5495

Cited by 137 publications

(101 citation statements)

References 41 publications

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“…It drives urgent need to detect new targets and treatment strategies. MiRNAs play a vital role in tumorigenesis, angiogenesis and drug resistance [32–34], and are proved to be a useful biomarker in the diagnosis and prognosis of cancer. Recently, miRNAs or anti-miRNAs trafficked by microvesicles (MV) or other plasmids have been used for the treatment of various diseases in mouse models, including cancers [22, 35, 36].…”

Section: Discussionmentioning

confidence: 99%

Onco-miR-130 promotes cell proliferation and migration by targeting TGFβR2 in gastric cancer

Duan

Zhang

et al. 2016

Oncotarget

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MicroRNAs (miRNAs) have been proved to play crucial roles in tumorigenesis. TGFβ signal pathway abnormality is found in various cancers and correlates with tumor proliferation and metastasis. However, the mechanisms underlying the dys-regulation of TGFβR2 expression in GC have not been investigated yet. In this study, we found that the TGFβR2 protein was clearly repressed in tumor tissues, while miR-130 expression level was dramatically increased in GC tissues. Firefly luciferase activity assay revealed that miR-130 could directly bind to 3′UTR of TGFβR2 mRNA. Meanwhile, miR-130 mimics lead to the decreased TGFβR2 protein levels, while miR-130 inhibitors enhanced TGFβR2 expression in SGC7901 cells. Subsequent functional experiments showed that overexpressed miR-130 could promote proliferation and migration of SGC7901 cells. And siRNA-mediated TGFβR2 down-regulation could simulate the effects of miR-130 mimics on phenotypes of SGC7901 cells. Furthermore, there existed intense relationship between the expression level of miR-130 and epithelial-mesenchymal markers. Our results demonstrated that miR-130 was an oncogene by directly targeting TGFβR2 in GC.

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Section: Discussionmentioning

confidence: 99%

Onco-miR-130 promotes cell proliferation and migration by targeting TGFβR2 in gastric cancer

Duan

Zhang

et al. 2016

Oncotarget

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“…In fact, miR‐21 mediates both trastuzumab and chemotherapy resistance in solid tumors via several mechanisms. It activates the IL‐6 – STAT3 – NF‐κB pathway and triggers PI3K ‐mediated signaling (De Mattos‐Arruda et al, ; Figure ). These data suggest that miR‐21 signaling sustains EMT and affects the tumor‐associated immune responses in HER2 + breast cancer.…”

Section: Mirnas and Resistance To Trastuzumabmentioning

confidence: 99%

MicroRNAs in cancer drug resistance: Basic evidence and clinical applications

Ghasabi

Mansoori

Mohammadi

et al. 2018

Journal Cellular Physiology

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Development of drug resistance has considerably limited the efficacy of cancer treatments, including chemotherapy and targeted therapies. Hence, understanding the molecular mechanisms underpinning the innate or the acquired resistance to these therapies is critical to improve drug efficiency and clinical outcomes. Several studies have implicated microRNAs (miRNA) in this process. MiRNAs repress gene expression by specific binding to complementary sequences in the 3' region of target messenger RNAs (mRNAs), followed by target mRNA degradation or blocked translation. By targeting molecules specific to a particular pathway within tumor cells, the new generation of cancer treatment strategies has shown significant advantages over conventional chemotherapy. However, the long-term efficacy of targeted therapies often remains poor, because tumor cells develop resistance to such therapeutics. Targeted therapies often involve monoclonal antibodies (mAbs), such as those blocking the ErB/HER tyrosine kinases, epidermal growth factor receptor (cetuximab) and HER2 (trastuzumab), and those inhibiting vascular endothelial growth factor receptor signaling (e.g., bevacizumab). Even though these are among the most used agents in tumor medicine, clinical response to these drugs is reduced due to the emergence of drug resistance as a result of toxic effects in the tumor microenvironment. Research on different types of human cancers has revealed that aberrant expression of miRNAs promotes resistance to the aforementioned drugs. In this study, we review the mechanisms of tumor cell resistance to mAb therapies and the role of miRNAs therein. Emerging treatment strategies combine therapies using innovative miRNA mimics or antagonizers with conventional approaches to maximize outcomes of patients with cancer.

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“…8, 9, 10 Previous studies have revealed that numerous miRNAs are upregulated or downregulated in breast cancer, contributing to the initiation and development of the disease, as well as its drug sensitivity. 11, 12, 13 For instance, overexpression of miRNA-451 sensitizes breast cancer cells to doxorubicin, 14 and upregulation of miRNA-21 is associated with acquired trastuzumab resistance.…”

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confidence: 99%

miRNA-205 targets VEGFA and FGF2 and regulates resistance to chemotherapeutics in breast cancer

et al. 2016

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MicroRNAs (miRNAs) have critical roles in regulating cancer cell survival, proliferation and sensitivity to chemotherapy. The potential application of using miRNAs to predict chemotherapeutic response to cancer treatment is highly promising. However, the underlying mechanisms of chemotherapy response control by miRNAs remain to be fully identified and their prognostic value has not been fully evaluated. Here we show a strong correlation between miR-205 expression and chemosensitivtiy to TAC (docetaxol, doxorubicin plus cyclophosphamide), a widely-used neoadjuvant chemotherapy (NAC) regimen, for breast cancer patients. High level of miR-205 predicted better response to TAC regimen NAC in breast cancer patients. We found miR-205 downregulated in both MCF-7/A02 and CALDOX cells, two drug-resistant derivatives of MCF-7 and Cal51 cells, and its ectopic expression led to an increase in apoptosis resensitization of both drug-resistant cell lines to doxorubicin and taxol. We further show that miR-205 directly binds VEGFA and FGF2 mRNA 3′-UTRs and confirm that miR-205 levels are negatively correlated with VEGFA and FGF2 mRNA expression in breast cancer patients. Adding VEGFA and FGF2 exogenously to chemosensitive breast cancer cells and chemoresistant cells with miR-205 overexpression led to drug resistance. Consistently, low VEGFA and FGF2 expression correlated with better response to NAC in breast cancer patients. In addition, inhibition of tumor growth and resensitization to doxorubicin were also observed in mouse tumor xenografts from cells overexpressing miR-205. Taken together, our data suggest that miR-205 enhances chemosensitivity of breast cancer cells to TAC chemotherapy by suppressing both VEGFA and FGF2, leading to evasion of apoptosis. MiR-205 may serve as a predictive biomarker and a potential therapeutic target in breast cancer treatment.

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MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients

Cited by 137 publications

References 41 publications

Onco-miR-130 promotes cell proliferation and migration by targeting TGFβR2 in gastric cancer

Onco-miR-130 promotes cell proliferation and migration by targeting TGFβR2 in gastric cancer

MicroRNAs in cancer drug resistance: Basic evidence and clinical applications

miRNA-205 targets VEGFA and FGF2 and regulates resistance to chemotherapeutics in breast cancer

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