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MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1.
- Source :
-
Oncogene [Oncogene] 2016 Dec 01; Vol. 35 (48), pp. 6189-6202. Date of Electronic Publication: 2016 May 09. - Publication Year :
- 2016
-
Abstract
- ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2-positive). Enhanced ErbB-2 expression was also found in gastric cancer (GC) and has been correlated with poor clinical outcome. The ErbB-2-targeted therapies trastuzumab (TZ), a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor, have proved highly beneficial. However, resistance to such therapies remains a major clinical challenge. We here revealed a novel mechanism underlying the antiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation of miR-16. Forced expression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ and lapatinib, as well as in a preclinical BC model resistant to these agents. This reveals miR-16 role as tumor suppressor in ErbB-2-positive BC and GC. Using genome-wide expression studies and miRNA target prediction algorithms, we identified cyclin J and far upstream element-binding protein 1 (FUBP1) as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supporting the clinical relevance of our results, we found that high levels of miR-16 and low or null FUBP1 expression correlate with TZ response in ErbB-2-positive primary BCs. These findings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivity to TZ therapy. Furthermore, we revealed miR-16 as an innovative therapeutic agent for TZ- and lapatinib-resistant ErbB-2-positive BC and GC.
- Subjects :
- 3' Untranslated Regions
Animals
Antineoplastic Agents pharmacology
Binding Sites
Breast Neoplasms drug therapy
Breast Neoplasms metabolism
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Drug Resistance, Neoplasm genetics
Female
Genes, Tumor Suppressor
Humans
Lapatinib
Male
Mice
Models, Biological
Promoter Regions, Genetic
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-myc metabolism
RNA Interference
RNA-Binding Proteins
Receptor, ErbB-2 antagonists & inhibitors
Receptor, ErbB-2 metabolism
Stomach Neoplasms drug therapy
Stomach Neoplasms metabolism
Breast Neoplasms genetics
Cyclins genetics
DNA Helicases genetics
DNA-Binding Proteins genetics
Gene Expression Regulation, Neoplastic drug effects
MicroRNAs genetics
Quinazolines pharmacology
Stomach Neoplasms genetics
Trastuzumab pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 35
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 27157613
- Full Text :
- https://doi.org/10.1038/onc.2016.151