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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.

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.

SUBMITTER: Venturutti L

PROVIDER: S-EPMC5832962 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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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.

Venturutti L L Cordo Russo R I RI Rivas M A MA Mercogliano M F MF Izzo F F Oakley R H RH Pereyra M G MG De Martino M M Proietti C J CJ Yankilevich P P Roa J C JC Guzmán P P Cortese E E Allemand D H DH Huang T H TH Charreau E H EH Cidlowski J A JA Schillaci R R Elizalde P V PV

Oncogene 20160509 48

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 anti ...[more]

PMID: 27157613

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Project description:The newly developed concept of oncogene addiction provides a rationale for the use of targeted therapies. In sharp contrast to the field of breast cancer treatment, attempts to target human epidermal growth factor receptor 2 (HER2) among gastric cancer (GC) patients have been unsatisfactory. The ToGA trial reported only a modest prolongation of progression-free survival (PFS) with trastuzumab and the subsequent TYTAN and LOGiC trials failed to demonstrate any survival advantage with lapatinib. These results suggest that a response to the molecular-targeted therapies is achieved in only a fraction of the patients; in addition, even responders may experience secondary resistance, with the efficacy of the treatment being decreased or abrogated over a short period of time. Considering the increased recognition of primary or acquired resistance, recent investigations on targeted therapies have been primarily focused on determining in advance the mechanisms that may mediate resistance to treatment and the methods through which such obstacles may be circumvented. The proposed molecules or mechanisms that may be responsible for the development of resistance to single HER2-targeted therapy include a dimerization partner or crosstalk with HER2, such as HER3 and MET, as well as any subsequent activation of their downstream pathways, which exhibit a partial overlap with those of HER2. Furthermore, genetic alterations that stimulate the aberrant activation of the pathways downstream of HER2 may be the underlying mechanisms that restore prosurvival signaling. These mechanisms generate a complex signaling network with a significant potential for signal amplification and diversification. Although in the early stages of description, several compounds have been suggested as next generation treatments for GC, with expectations for their delineating the function of such receptors or molecules, with subsequent contributions of specific survival signaling blockades. This review focuses on the current achievements of anti-HER2 therapies in GC and the plausible mechanisms of resistance to these therapies. Elucidating these mechanisms of resistance may provide valuable information pertinent to the design of future strategies to improve molecular-targeted therapies.

Project description:BackgroundIn breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% of the patients. For therapeutic intervention, ERBB2 is targeted by monoclonal antibody trastuzumab in adjuvant settings; however, de novo resistance to this antibody is still a serious issue, requiring the identification of additional targets to overcome resistance. In this study, we have combined computational simulations, experimental testing of simulation results, and finally reverse engineering of a protein interaction network to define potential therapeutic strategies for de novo trastuzumab resistant breast cancer.ResultsFirst, we employed Boolean logic to model regulatory interactions and simulated single and multiple protein loss-of-functions. Then, our simulation results were tested experimentally by producing single and double knockdowns of the network components and measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting of ERBB2 and EGFR did not affect the response to trastuzumab in de novo resistant cells, which might be due to decoupling of receptor activation and cell cycle progression. Furthermore, examination of c-MYC in resistant as well as in sensitive cell lines, using a specific chemical inhibitor of c-MYC (alone or in combination with trastuzumab), demonstrated that both trastuzumab sensitive and resistant cells responded to c-MYC perturbation.ConclusionIn this study, we connected ERBB signaling with G1/S transition of the cell cycle via two major cell signaling pathways and two key transcription factors, to model an interaction network that allows for the identification of novel targets in the treatment of trastuzumab resistant breast cancer. Applying this new strategy, we found that, in contrast to trastuzumab sensitive breast cancer cells, combinatorial targeting of ERBB receptors or of key signaling intermediates does not have potential for treatment of de novo trastuzumab resistant cells. Instead, c-MYC was identified as a novel potential target protein in breast cancer cells.

Dataset Information

MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1.

Publications

MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1.

Similar Datasets

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