TY - JOUR
T1 - MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients
AU - de Mattos-Arruda, Leticia
AU - Bottai, Giulia
AU - Nuciforo, Paolo G.
AU - di Tommaso, Luca
AU - Giovannetti, Elisa
AU - Peg, Vicente
AU - Losurdo, Agnese
AU - Pérez-Garcia, José
AU - Masci, Giovanna
AU - Corsi, Fabio
AU - Cortés, Javier
AU - Seoane, Joan
AU - Calin, George A.
AU - Santarpia, Libero
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Epithelial-to-mesenchymal transition
KW - HER2-overexpressing breast cancers
KW - MicroRNA-21
KW - Resistance to neoadjuvant trastuzumab-chemotherapy
KW - Tumor-associated immune response
UR - http://www.scopus.com/inward/record.url?scp=84947808033&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947808033&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.5495
DO - 10.18632/oncotarget.5495
M3 - Article
C2 - 26452030
AN - SCOPUS:84947808033
SN - 1949-2553
VL - 6
SP - 37269
EP - 37280
JO - Oncotarget
JF - Oncotarget
IS - 35
ER -