The Experts below are selected from a list of 92073 Experts worldwide ranked by ideXlab platform
Kenneth P. Nephew - One of the best experts on this subject based on the ideXlab platform.
-
microRNA 221 222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways
Oncogene, 2011Co-Authors: Xi Rao, G Di Leva, F Fang, C Devlin, M E Burow, M Ivan, C M Croce, Corinna Hartmanfrey, Kenneth P. NephewAbstract:Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two 'oncomirs' may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.
-
abstract 4723 microRNA 221 222 confer breast cancer resistance to fulvestrant by targeting multiple oncogenic activities
Cancer Research, 2009Co-Authors: Xi Rao, G Di Leva, F Fang, C M Croce, Corinna Hartmanfrey, Curtis Balch, John P Thomson, Scott M Hammond, Yunlong Liu, Kenneth P. NephewAbstract:Breast cancer is the leading cause of female death worldwide and will afflict 1 of 8 U.S. women in their lifetime. One commonly used breast cancer therapy, fulvestrant, has potent activity against hormone-sensitive breast cancers. However, almost all patients eventually develop resistance to fulvestrant, and the underlying mechanism(s) of loss of drug response remains unknown. We had previously generated a fulvestrant-resistant cell line (MCF7-F) highly characteristic of this clinical phenomenon (Cancer Res, 66, 2006). microRNAs, 19-22-nucleotide non-coding regulatory RNAs, have recently been implicated in breast cancer, and we subjected MCF7-F cells to microRNA expression analysis using a 612-feature custom microarray. From those analyses, we determined that two specific microRNAs, miR-221 and miR-222, were significantly upregulated by 9-fold and 6-fold respectively in MCF7-F cells (as compared to the parental MCF7 cell line). To further assess the role of miR-221/222 in MCF7-F cells, we downregulated miR-221/222 by using chemically stable, antisense oligoribonucleotides (\#8220;antagomirs\#8221;) against those specific microRNA sequences, demonstrating that miR-221/222 antagomir treatment significantly decreased cell proliferation by 40%. In addition, the cyclin-dependent kinase inhibitor (and tumor suppressor) p27(Kip1) (CDKN1B, a known target protein for miR-221/222), which is downregulated in MCF7-F, was upregulated after antagomir treatment, with cell cycle analyses demonstrating G1 cell cycle arrest. Based on this evidence, we hypothesize that miR-221/222 upregulation contributes to the development of fulvestrant resistance, leading to loss of p27(Kip1), which subsequently facilitates estrogen-independent cell cycle progression. However, as any single microRNA likely targets numerous genes to influence the overall malignant phenotype, we sought to identify additional miR-221/222 targets in MCF7-F cells. MCF7-F cells were treated with miR-221/222 antagomirs, and then subjected to Affymetrix gene expression profiling and pathway enrichment analysis. Several well known signaling pathways appeared to be regulated by miR-221/222, including p53, TGF-beta, Notch and MAPK. We are currently validating the regulatory role of miR-221/222 in these pathways and investigating their role in the development of fulvestrant resistance. Overall, the findings indicate that miR-221 and miR-222 may represent promising therapeutic targets for fulvestrant resensitization in patients with advanced breast cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4723.
Federica Felicetti - One of the best experts on this subject based on the ideXlab platform.
-
microRNA 221 and 222 pathway controls melanoma progression
Expert Review of Anticancer Therapy, 2008Co-Authors: Federica Felicetti, Cristina M Errico, Patrizia Segnalini, Gianfranco Mattia, Alessandra CareAbstract:microRNAs (miRNAs) represent a new family of small noncoding RNAs that negatively regulate gene expression. Recent studies demonstrated miRNA involvement in all the main biological processes, including tumor development as a consequence of an aberrant deregulated expression. Growing evidence is showing the capability of miRNA expression profiles to unequivocally distinguish between normal and neoplastic tissues, leading to the identification of new diagnostic and/or prognostic molecular markers. In addition, miRNAs might eventually represent new targets to aim at as innovative therapeutic approaches, particularly relevant in those types of cancer, such as melanoma, which are still lacking effective traditional therapies. In particular, the inhibition of miRNA-221 and -222, which are abnormally expressed in melanoma and favor the induction of the malignant phenotype by downregulating c-KIT receptor and p27Kip, might in the future represent an efficient treatment for translation into the clinical setting.
-
the promyelocytic leukemia zinc finger microRNA 221 222 pathway controls melanoma progression through multiple oncogenic mechanisms
Cancer Research, 2008Co-Authors: Federica Felicetti, Patrizia Segnalini, Gianfranco Mattia, Maria Cristina Errico, Lisabianca Bottero, Antonella Stoppacciaro, Mauro Biffoni, Nadia Felli, M Petrini, Mario P ColomboAbstract:The incidence of cutaneous melanoma is steadily increasing. Although several molecular abnormalities have been associated with melanoma progression, the mechanisms underlying the differential gene expression are still largely unknown and targeted therapies are not yet available. Noncoding small RNAs, termed microRNAs (miR), have been recently reported to play important roles in major cellular processes, including those involved in cancer development and progression. We have identified the promyelocytic leukemia zinc finger (PLZF) transcription factor as a repressor of miR-221 and miR-222 by direct binding to their putative regulatory region. Specifically, PLZF silencing in melanomas unblocks miR-221 and miR-222, which in turn controls the progression of the neoplasia through down-modulation of p27Kip1/CDKN1B and c-KIT receptor, leading to enhanced proliferation and differentiation blockade of the melanoma cells, respectively. In vitro and in vivo functional studies, including the use of antisense “antagomir” oligonucleotides, confirmed the key role of miR-221/-222 in regulating the progression of human melanoma; this suggests that targeted therapies suppressing miR-221/-222 may prove beneficial in advanced melanoma. [Cancer Res 2008;68(8):2745–10]
C M Croce - One of the best experts on this subject based on the ideXlab platform.
-
microRNA 221 222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways
Oncogene, 2011Co-Authors: Xi Rao, G Di Leva, F Fang, C Devlin, M E Burow, M Ivan, C M Croce, Corinna Hartmanfrey, Kenneth P. NephewAbstract:Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two 'oncomirs' may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.
-
microRNA 221 targets bmf in hepatocellular carcinoma and correlates with tumor multifocality
Clinical Cancer Research, 2009Co-Authors: Laura Gramantieri, C M Croce, Francesca Fornari, Manuela Ferracin, Angelo Veronese, Silvia Sabbioni, George A Calin, Gian Luca Grazi, Luigi BolondiAbstract:Deregulated cell proliferation and apoptosis play a major role in hepatocellular carcinoma (HCC). microRNAs participate in the modulation of key molecules linked to hepatocarcinogenesis. Purpose: This study aims to investigate the role of miR-221 in the modulation of Bmf, a proapoptotic BH3-only protein, and to characterize miR-221 contribution to hepatocarcinogenesis through modulation of apoptosis. Experimental Design: Transfection of miR-221 and anti-miR-221 in HCC-derived cell lines and luciferase reporter assay were used to assess Bmf as a target of miR-221. Modulation of miR-221 and Bmf expression contributed to characterize their role in anoikis. Primary HCC tissues were analyzed to assess the clinical relevance of in vitro findings. Results: Enforced miR-221 expression caused Bmf down-regulation, whereas anti-miR-221 induced its up-regulation. A luciferase reporter assay confirmed Bmf as a target of miR-221. Following matrix detachment, miR-221 silencing led to increased apoptotic cell death. The analysis of HCC tissues revealed an inverse correlation between miR-221 and Bmf expression and a direct correlation between Bmf and activated caspase-3, as a marker of apoptosis. High miR-221 levels were associated with tumor multifocality and reduced time to recurrence after surgery. Conclusions: Our results indicate that miR-221, by targeting Bmf, inhibits apoptosis. Moreover, in HCC, miR-221 overexpression is associated with a more aggressive phenotype. These findings, together with the previously reported modulation of CDKN1B/p27 and CDKN1C/p57, show that miR-221 simultaneously affects multiple pro-oncogenic pathways and suggest miR-221 as a potential target for nonconventional treatment against HCC. (Clin Cancer Res 2009;15(16):5073–81)
-
abstract 4723 microRNA 221 222 confer breast cancer resistance to fulvestrant by targeting multiple oncogenic activities
Cancer Research, 2009Co-Authors: Xi Rao, G Di Leva, F Fang, C M Croce, Corinna Hartmanfrey, Curtis Balch, John P Thomson, Scott M Hammond, Yunlong Liu, Kenneth P. NephewAbstract:Breast cancer is the leading cause of female death worldwide and will afflict 1 of 8 U.S. women in their lifetime. One commonly used breast cancer therapy, fulvestrant, has potent activity against hormone-sensitive breast cancers. However, almost all patients eventually develop resistance to fulvestrant, and the underlying mechanism(s) of loss of drug response remains unknown. We had previously generated a fulvestrant-resistant cell line (MCF7-F) highly characteristic of this clinical phenomenon (Cancer Res, 66, 2006). microRNAs, 19-22-nucleotide non-coding regulatory RNAs, have recently been implicated in breast cancer, and we subjected MCF7-F cells to microRNA expression analysis using a 612-feature custom microarray. From those analyses, we determined that two specific microRNAs, miR-221 and miR-222, were significantly upregulated by 9-fold and 6-fold respectively in MCF7-F cells (as compared to the parental MCF7 cell line). To further assess the role of miR-221/222 in MCF7-F cells, we downregulated miR-221/222 by using chemically stable, antisense oligoribonucleotides (\#8220;antagomirs\#8221;) against those specific microRNA sequences, demonstrating that miR-221/222 antagomir treatment significantly decreased cell proliferation by 40%. In addition, the cyclin-dependent kinase inhibitor (and tumor suppressor) p27(Kip1) (CDKN1B, a known target protein for miR-221/222), which is downregulated in MCF7-F, was upregulated after antagomir treatment, with cell cycle analyses demonstrating G1 cell cycle arrest. Based on this evidence, we hypothesize that miR-221/222 upregulation contributes to the development of fulvestrant resistance, leading to loss of p27(Kip1), which subsequently facilitates estrogen-independent cell cycle progression. However, as any single microRNA likely targets numerous genes to influence the overall malignant phenotype, we sought to identify additional miR-221/222 targets in MCF7-F cells. MCF7-F cells were treated with miR-221/222 antagomirs, and then subjected to Affymetrix gene expression profiling and pathway enrichment analysis. Several well known signaling pathways appeared to be regulated by miR-221/222, including p53, TGF-beta, Notch and MAPK. We are currently validating the regulatory role of miR-221/222 in these pathways and investigating their role in the development of fulvestrant resistance. Overall, the findings indicate that miR-221 and miR-222 may represent promising therapeutic targets for fulvestrant resensitization in patients with advanced breast cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4723.
Lianfeng Zhang - One of the best experts on this subject based on the ideXlab platform.
-
correction microRNA 221 inhibits autophagy and promotes heart failure by modulating the p27 cdk2 mtor axis
Cell Death & Differentiation, 2021Co-Authors: Jing Wang, Chengfeng Wang, Xin Wang, W Dong, W Qiu, Y Wang, X Zhao, Yubao Zou, Li Song, Lianfeng ZhangAbstract:Since online publication of this article, the authors noticed that there were errors in the images used to compile Fig. 3c, 3g, and Supplementary Fig. 3g.
-
microRNA 221 inhibits autophagy and promotes heart failure by modulating the p27 cdk2 mtor axis
Cell Death & Differentiation, 2015Co-Authors: Jing Wang, Chengfeng Wang, Xin Wang, W Dong, W Qiu, Y Wang, X Zhao, Yubao Zou, Li Song, Lianfeng ZhangAbstract:microRNAs have emerged as crucial regulators of cardiac homeostasis and remodeling in various cardiovascular diseases. We previously demonstrated that miR-221 regulated cardiac hypertrophy in vitro. In the present study, we demonstrated that the cardiac-specific overexpression of miR-221 in mice evoked cardiac dysfunction and heart failure. The lipidated form of microtubule-associated protein 1 light chain 3 was significantly decreased and sequestosome 1 was accumulated in cardiac tissues of transgenic (TG) mice, indicating that autophagy was impaired. Overexpression of miR-221 in vitro reduced autophagic flux through inhibiting autophagic vesicle formation. Furthermore, mammalian target of rapamycin (mTOR) was activated by miR-221, both in vivo and in vitro. The inactivation of mTOR abolished the miR-221-induced inhibition of autophagy and cardiac remodeling. Our previous study has demonstrated that cyclin-dependent kinase (CDK) inhibitor p27 was a direct target of miR-221 in cardiomyocytes. Consistently, the expression of p27 was markedly suppressed in the myocardia of TG mice. Knockdown of p27 by siRNAs was sufficient to mimic the effects of miR-221 overexpression on mTOR activation and autophagy inhibition, whereas overexpression of p27 rescued miR-221-induced autophagic flux impairment. Inhibition of CDK2 restored the impaired autophagic flux and rescued the cardiac remodeling induced by either p27 knockdown or miR-221 overexpression. These findings reveal that miR-221 is an important regulator of autophagy balance and cardiac remodeling by modulating the p27/CDK2/mTOR axis, and implicate miR-221 as a therapeutic target in heart failure.
Sarmila Majumder - One of the best experts on this subject based on the ideXlab platform.
-
microRNA 221 222 confers tamoxifen resistance in breast cancer by targeting p27 kip1
Cancer Research, 2009Co-Authors: Sarmila Majumder, Kalpana Ghoshal, Tyler E Miller, Bhuvaneswari Ramaswamy, Satavisha Roy, Jharna Datta, Charles L Shapiro, Samson T JacobAbstract:CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #3023 Background: Breast cancer is the most common malignancy in women, accounting for 31% of all female cancers. Over two-thirds of breast cancers exhibit high concentrations of estrogen receptor, which contribute to tumor growth and progression. Blocking the steroid hormone pathway with tamoxifen and/or oophorectomy has been shown to be effective in this patient population. However, approximately 30% of the breast cancer is resistant to tamoxifen. Recent studies have highlighted the key regulatory roles of microRNAs (miR) in all fundamental cellular processes in animals and plants including primary human cancers. We hypothesized that alteration in the expression of specific miRs in breast cancer could contribute to tamoxifen resistance. Methods: To test this hypothesis, we performed microRNA microarray analysis using MCF-7 cell lines that are either sensitive (parental) or resistant to tamoxifen (4-hydroxy tamoxifen resistant-OHTR). Using Real-time RT-PCR we validated altered expression of the miRs in both the cell culture model and the primary human breast cancer tissues. Cells overexpressing miR-221/222 or p27(kip1) were created by transfection of mammalian expression vectors using Lipofectamine2000 followed by G418 selection. Cell viability upon tamoxifen treatment was measured by MTT assay, extent of apoptosis was monitored by Western blot analysis of PAPR and Caspase cleavage and cell cycle profile was studied using Flow cytometry. Results: Eight miRs were found to be significantly upregulated while seven miRs were significantly down-regulated in the OHTR cells compared to parental MCF-7 cells. The increased expression of three upregulated (miR-221, miR-222 and miR-181) and three downregulated (miR-21, miR-342 and miR-489) miRs was later validated in the cell lines by real-time RT-PCR. In addition, the level of miR-221 and miR-222 was significantly elevated in Her2/neu(+) primary human breast cancer tissues, compared to Her2/neu(-) tissue samples. The Her2/neu expressing tumors are known to be relatively resistant to endocrine therapy. Ectopic expression of miR-221/miR-222 in parental MCF-7 cells rendered the cells more tolerant to tamoxifen than the control cells. The cell cycle inhibitor p27/Kip1, a known target of miR-221/miR-222 was significantly reduced in both OHTR cells and miR-221/222 overexpressing MCF-7 cells, which was consistent with the upregulation of the miRs. Ectopic expression of p27/Kip1 in the resistant OHTR cells enhanced cell death when exposed to tamoxifen. Conclusion: This study has revealed a specific miR signature for the tamoxifen-resistant breast cancer and an important cell cycle inhibitor target of the altered miR, which could be used as a prognostic marker for the drug-resistant breast cancer. Further studies of other miRs differentially expressed in tamoxifen resistant cell lines, will help us not only in identifying such patients but also may serve as a therapeutic target in the future. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3023.
-
microRNA 221 222 confers tamoxifen resistance in breast cancer by targeting p27kip1
Journal of Biological Chemistry, 2008Co-Authors: Tyler E Miller, Kalpana Ghoshal, Samson T Jacob, Bhuvaneswari Ramaswamy, Satavisha Roy, Jharna Datta, Charles L Shapiro, Sarmila MajumderAbstract:We explored the role of microRNAs (miRNAs) in acquiring resistance to tamoxifen, a drug successfully used to treat women with estrogen receptor-positive breast cancer. miRNA microarray analysis of MCF-7 cell lines that are either sensitive (parental) or resistant (4-hydroxytamoxifen-resistant (OHTR)) to tamoxifen showed significant (>1.8-fold) up-regulation of eight miRNAs and marked down-regulation (>50%) of seven miRNAs in OHTR cells compared with parental MCF-7 cells. Increased expression of three of the most promising up-regulated (miR-221, miR-222, and miR-181) and down-regulated (miR-21, miR-342, and miR-489) miRNAs was validated by real-time reverse transcription-PCR. The expression of miR-221 and miR-222 was also significantly (2-fold) elevated in HER2/neu-positive primary human breast cancer tissues that are known to be resistant to endocrine therapy compared with HER2/neu-negative tissue samples. Ectopic expression of miR-221/222 rendered the parental MCF-7 cells resistant to tamoxifen. The protein level of the cell cycle inhibitor p27Kip1, a known target of miR-221/222, was reduced by 50% in OHTR cells and by 28–50% in miR-221/222-overexpressing MCF-7 cells. Furthermore, overexpression of p27Kip1 in the resistant OHTR cells caused enhanced cell death when exposed to tamoxifen. This is the first study demonstrating a relationship between miR-221/222 expression and HER2/neu overexpression in primary breast tumors that are generally resistant to tamoxifen therapy. This finding also provides the rationale for the application of altered expression of specific miRNAs as a predictive tamoxifen-resistant breast cancer marker.