Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

Venturutti, Leandro; Romero, Lucía Virginia; Urtreger, Alejandro J.; Chervo, María Florencia; Russo, R; Mercogliano, María F.; Inurrigarro, Gloria; Pereyra, Matías G.; Proietti, Cecilia J.; Izzo, Franco; Flaqué, María Celeste Díaz; Sundblad, Victoria; Roa, Juan Carlos; Guzmán, Pablo; Joffé, Elisa D. Bal de Kier; Charreau, Eduardo H.; Schillaci, Roxana; Elizalde, Patricia V.

doi:10.1038/onc.2015.281

Cited by 54 publications

(54 citation statements)

References 80 publications

(140 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…57 Our own findings demonstrated that ErbB-2 nuclear function as a coactivator of Stat3 and as a transcription factor are mandatory for miR-21 upregulation. 58 Interestingly, several of the tumor types which, in addition to BC and GC, show ErbB-2 gene amplification or protein overexpression, display low levels of miR-16. 59–65 Given that miR-16 was found to act as a tumor suppressor in these cancers, 59–65 our findings raise the exciting possibility that ErbB-2 inhibition of miR-16 expression may be a common mechanism underlying ErbB-2-driven cancer growth.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Reverse transcriptase (RT)–quantitative PCR (qPCR) was performed as described. 58 Details are provided in Supplementary Materials and methods.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…STAT3 co-opts the function of nuclear HER2 by recruiting it as its co-activator at the response elements in the promoter of miR-21. miR-21, in turn, was found to downregulate the expression of the metastasis suppressor protein PDCD4 in breast cancer (52). Further studies disclosed that serum and urine miR-21 may be a potential diagnostic biomarker for breast cancer; however, prior to its implementation in the clinic, further investigation is warranted (53,54).…”

Section: Mir-21 and Solid Tumorsmentioning

confidence: 99%

Emerging role of microRNA-21 in cancer

2016

View full text Add to dashboard Cite

Abstract. MicroRNAs (miRs) are a class of single-stranded RNA molecules of 15-27 nucleotides in length that regulate gene expression at the post-translational level. miR-21 is one of the earliest identified cancer-promoting 'oncomiRs', targeting numerous tumor suppressor genes associated with proliferation, apoptosis and invasion. The regulation of miR-21 and its role in carcinogenesis have been extensively investigated. Recent studies have focused on the diagnostic and prognostic value of miR-21 as well as its implication in the drug resistance of human malignancies. The further use of miR-21 as a biomarker and target for cancer treatments is likely to improve the outcome for patients with cancer. The present review highlights recent findings associated with the importance of miR-21 in hematological and non-hematological malignancies. IntroductionMicroRNAs (miRs) are a class of naturally occurring short non-coding RNA molecules of 15-27 nucleotides in length that regulate eukaryotic gene expression at the post-transcriptional level. Almost 2,000 human miRNAs have been identified through cloning and/or sequence analysis (1). They have key regulatory roles in the development, differentiation and apoptosis of normal cells, as well as in the determination of the final phenotype of cancer cells, affecting carcinogenesis and metastatic potential (2). miR-21 is an abundantly expressed miRNA in mammalian cells, whose upregulation is associated with numerous types of cancer (3,4). By generation of a conditional miR-21 knock-in mouse, it was demonstrated that miR-21 functions as an oncogene with its overexpression resulting in malignant B-cell lymphoma (5). Indeed, miR-21 was found to be the only consistently upregulated miRNA in a study that profiled 540 clinical samples from cancer patients (6). The majority of studies on miR-21 have focused on its role in carcinogenesis and its clinical application. miR-21 is also expressed in hematopoietic cells of the immune system, including B/T cells, monocytes, macrophages and dendritic cells. High miR-21 levels are, therefore, considered to be a marker of immune cell activation (7). Regarding pathological necrosis, miR-21 enhances cellular necrosis by negatively regulating tumor suppressor genes associated with the death receptor-mediated intrinsic apoptotic pathway (8). Biological function of miR-21The biological functions of various miRNAs, including miR-21, have been extensively investigated and miR-21 is

show abstract

“…microRNA 21, also known as hsamir-21 or miRNA 21 is encoded by the miR-21 gene located on chromosome 17q23.2 immediately downstream of the vacuole membrane protein-1 (VMP1) gene [4,6]. miR-21 is a common microRNA that is upregulated in a wide variety of cancers, including breast [13] ovaries [14] cervix [15] colon [16] lung [17] and liver [18]. In addition, it has been identified that miR-21 is consistently upregulated in several types of human cancers, including the stomach, as compared with matching non-cancerous tissue [19].miR-21 is also an oncogenic miRNA that can modulate the expression of multiple tumour suppressor genes, such as phosphatase and tensin homolog (PTEN), Serpini1, and programmed cell death 4 protein (PDCD4) [20,21].…”

Section: Introductionmentioning

confidence: 99%