MicroRNA-21 Links Epithelial-to-mesenchymal Transition And Inflammatory Signals To Confer Resistance To Neoadjuvant Trastuzumab And Chemotherapy In HER2-positive Breast Cancer Patients
L. De Mattos-Arruda, G. Bottai, P. Nuciforo, L. Di Tommaso, E. Giovannetti, V. Peg, A. Losurdo, J. Pérez-García, G. Masci, F. Corsi, J. Cortés, J. Seoane, G. Calin, L. Santarpia
Published 2015 · Medicine
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Patients with primary HER2-positive breast cancer benefit from HER2-targeted therapies. Nevertheless, a significant proportion of these patients die of disease progression due to mechanisms of drug resistance. MicroRNAs (miRNAs) are emerging as critical core regulators of drug resistance that act by modulating the epithelial-to-mesenchymal transition (EMT) and cancer-related immune responses. In this study, we investigated the association between the expression of a specific subset of 14 miRNAs involved in EMT processes and immune functions and the response to neoadjuvant trastuzumab and chemotherapy in 52 patients with HER2-overexpressing breast tumors. The expression of only a single miRNA, miR-21, was significantly associated with residual disease (p = 0.030) and increased after trastuzumab-chemotherapy (p = 0.012). A target prediction analysis coupled with in vitro and in vivo validations revealed that miR-21 levels inversely correlated with the expression of PTEN (rs = -0.502; p = 0.005) and PDCD4 (rs = -0.426; p = 0.019), which differentially influenced the drug sensitivity of HER2-positive breast cancer cells. However, PTEN expression was only marginally associated with residual disease. We further demonstrated that miR-21 was able to affect the response to both trastuzumab and chemotherapy, triggering an IL-6/STAT3/NF-κB-mediated signaling loop and activating the PI3K pathway. Our findings support the ability of miR-21 signaling to sustain EMT and shape the tumor immune microenvironment in HER2-positive breast cancer. Collectively, these data provide a rationale for using miR-21 expression as a biomarker to select trastuzumab-chemotherapy-resistant HER2-positive breast cancer patients who may benefit from treatments containing PI3K inhibitors or immunomodulatory drugs.
This paper references
Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.
David G. DeNardo (2011)
Treatment of HER2-positive breast cancer: current status and future perspectives
Carlos L. Arteaga (2012)
Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways
S. Zhang (2011)
DNA Damage Induces NF-κB-dependent MicroRNA-21 Up-regulation and Promotes Breast Cancer Cell Invasion*
Jixiao Niu (2012)
Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers.
Carsten Denkert (2015)
PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance
Howard M. Stern (2015)
Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy.
X-b Li (2008)
HER2-overexpressing breast cancer: time for the cure with less chemotherapy?
Sherene Loi (2011)
MiRNAs as biomarkers and therapeutic targets in cancer.
H M Heneghan (2010)
MicroRNAs regulate both epithelial-to-mesenchymal transition and cancer stem cells
P. Ceppi (2014)
PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer.
Ian J. Majewski (2015)
Resistance to Trastuzumab in Breast Cancer
Paula R Pohlmann (2009)
Down-regulation of programmed cell death 4 leads to epithelial to mesenchymal transition and promotes metastasis in mice.
Q. Wang (2013)
Effect of p95HER2/611CTF on the response to trastuzumab and chemotherapy.
J. Parra-Palau (2014)
Molecular determinants of trastuzumab efficacy: What is their clinical relevance?
Pradip De (2013)
Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion
D. Iliopoulos (2011)
MicroRNAs: toward the clinic for breast cancer patients.
M. Ferracin (2011)
MicroRNAs play a central role in molecular dysfunctions linking inflammation with cancer.
Esmerina Tili (2013)
STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits
S. Chung (2014)
A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages
Haihui Lu (2014)
Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With www
Phosphatase and tensin homolog deficiency and resistance to trastuzumab and chemotherapy.
Brent Neil Rexer (2013)
TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers.
B. Győrffy (2014)
Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population.
Hasan Korkaya (2012)
The interaction of anticancer therapies with tumor-associated macrophages
Alberto Mantovani (2015)
Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.
S. Loi (2014)
Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications.
B. Rexer (2012)
CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells
Delphine R. Boulbes (2015)
STAT3 activation in HER2-overexpressing breast cancer promotes Oncotarget 37279 www.impactjournals.com/oncotarget epithelial-mesenchymal transition and cancer stem cell traits
SS Chung (2014)
Hyaluronan-CD44 Interaction with Protein Kinase Cϵ Promotes Oncogenic Signaling by the Stem Cell Marker Nanog and the Production of MicroRNA-21, Leading to Down-regulation of the Tumor Suppressor Protein PDCD4, Anti-apoptosis, and Chemotherapy Resistance in Breast Tumor Cells*
L. Bourguignon (2009)
Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment.
E. M. Dijkgraaf (2013)
Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status.
Paolo Nuciforo (2015)
A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis.
Shicheng Su (2014)
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Subhra K. Biswas (2010)
Error in Figure. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial.
Combining immunotherapy and targeted therapies in cancer treatment
Matthew Vanneman (2012)
STAT3 activation in HER2-overexpressing breast cancer promotes www.impactjournals.com/oncotarget epithelial-mesenchymal transition and cancer stem cell traits
S S Chung (2014)
HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion
H. Korkaya (2008)
HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis.
Z. Hartman (2011)
PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.
Y. Nagata (2004)
STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer.
D. Iliopoulos (2010)
Breast cancer stem cells and epithelial mesenchymal plasticity - Implications for chemoresistance.
Cletus Pinto (2013)
Molecular Pathways: microRNAs, Cancer Cells, and Microenvironment
I. Berindan-Neagoe (2014)
This paper is referenced by
Mechanisms of Multidrug Resistance in Cancer Chemotherapy
Karol Bukowski (2020)
Role of miR-21 as an authentic oncogene in mediating drug resistance in breast cancer.
Shiva Najjary (2020)
Exosomes-mediate microRNAs transfer in breast cancer chemoresistance regulation.
Juliana Carla Carvalho Santos (2016)
Targeting microRNAs as key modulators of tumor immune response
L. Paladini (2016)
PD-L1, inflammation, non-coding RNAs, and neuroblastoma: Immuno-oncology perspective.
Palanisamy Nallasamy (2018)
Exosomes as mediators of platinum resistance in ovarian cancer
Jennifer H Crow (2017)
Immunomodulatory miRNAs in Cancer: Targeting of Immune Checkpoints and the Tumor Microenvironment.
Hany A Omar (2019)
Cytokine‐mediated therapeutic resistance in breast cancer
Chunli Tan (2018)
Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma
Kelly Gaudelot (2017)
MicroRNA-340-5p modulates cisplatin resistance by targeting LPAATβ in osteosarcoma
Li-qiang Song (2017)
Resistance to Trastuzumab in Clinical Her2 Breast Cancer: Possible Relation to Molecular Subtype and Cancer Stem Cells
Maha Baligh Zickri (2016)
Molecular subtype predicts incidence and prognosis of brain metastasis from breast cancer in SEER database
Yi-Jun Kim (2018)
Interrelation of the Circulating and Tissue MicroRNA-21 with Tissue PDCD4 Expression and the Invasiveness of Iraqi Female Breast Tumors
Meena M. Abdulhussain (2017)
Clinical Theragnostic Relationship between Drug-Resistance Specific miRNA Expressions, Chemotherapeutic Resistance, and Sensitivity in Breast Cancer: A Systematic Review and Meta-Analysis
Rama Jayaraj (2019)
MicroRNAs Involved in Carcinogenesis, Prognosis, Therapeutic Resistance, and Applications in Human Triple-Negative Breast Cancer
L. Ding (2019)
Berrin Papila Kundaktepe (2020)
Wound fluids affect miR-21, miR-155 and miR-221 expression in breast cancer cell lines, and this effect is partially abrogated by intraoperative radiation therapy treatment
K. Zaleska (2017)
Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway
Xiao Fu (2018)
Involvement of miR-451 in resistance to paclitaxel by regulating YWHAZ in breast cancer
W. Wang (2017)
Advances in the discovery of microRNA-based anticancer therapeutics: latest tools and developments
K. To (2019)
Tumor microenvironment and noncoding RNAs as co-drivers of epithelial-mesenchymal transition and cancer metastasis.
Kinan Drak Alsibai (2018)
Gene Expression and miRNAs Profiling: Function and Regulation in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer
Rasha M. Sareyeldin (2019)
Nanotechnology, in silico and endocrine-based strategy for delivering paclitaxel and miRNA: Prospects for the therapeutic management of breast cancer.
Mohammad Azam Ansari (2019)
The Pattern of microRNA Binding Site Distribution
Fangyuan Zhang (2017)
Electrochemical miRNAs Determination in Formalin-Fixed, Paraffin-Embedded Breast Tumor Tissues Association with HER2 Expression
Susana Campuzano (2016)
11PS04 is a new chemical entity identified by microRNA-based biosensing with promising therapeutic potential against cancer stem cells
Tania Aguado (2019)
Targeting noncoding RNAs in disease
Brian D Adams (2017)
Emerging targets in cancer drug resistance
Shashank Kumar (2019)
miR-134 targets PDCD7 to reduce E-cadherin expression and enhance oral cancer progression.
Shih-Yuan Peng (2018)
CRISPR Technology for Breast Cancer: Diagnostics, Modeling, and Therapy
Rachel L. Mintz (2018)
Regulation of epithelial-mesenchymal transition through microRNAs: clinical and biological significance of microRNAs in breast cancer
Fu Peng (2016)
miRNA-205 targets VEGFA and FGF2 and regulates resistance to chemotherapeutics in breast cancer
Yunzhi Hu (2016)See more