Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer

TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in...

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Published inNature nanotechnology Vol. 14; no. 4; pp. 388 - 397
Main Authors Xu, Jiangsheng, Liu, Yunhua, Li, Yujing, Wang, Hai, Stewart, Samantha, Van der Jeught, Kevin, Agarwal, Pranay, Zhang, Yuntian, Liu, Sheng, Zhao, Gang, Wan, Jun, Lu, Xiongbin, He, Xiaoming
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.04.2019
Nature Publishing Group
Subjects
631/61/350/354
631/61/54/152
639/925/352/2733
Animals
Bioavailability
Breast cancer
Cancer
Cell Line, Tumor
Cell Proliferation
Chemistry and Materials Science
DNA-Directed RNA Polymerases - metabolism
Endosomes - metabolism
Female
Gene Deletion
Humans
Hydrogen-Ion Concentration
Inactivation
Lysosomes - metabolism
Materials Science
Mice, Inbred C57BL
Mice, Nude
Nanoparticles
Nanoparticles - chemistry
Nanoparticles - ultrastructure
Nanotechnology
Nanotechnology and Microengineering
p53 Protein
pH effects
Ribonucleic acid
RNA
siRNA
Therapy
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - enzymology
Triple Negative Breast Neoplasms - pathology
Tumor Suppressor Protein p53 - metabolism
Tumors
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Abstract TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified POLR2A in the TP53 -neighbouring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of POLR2A siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles leads to enhanced growth reduction of tumours characterized by hemizygous POLR2A loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise POLR2A targeted therapy in TNBC harbouring the common TP53 genomic alteration. Inhibiting POLR2A expression upon siRNA delivery represents a promising therapeutic strategy for triple negative breast cancers characterized by p53 inactivation.
AbstractList TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified POLR2A in the TP53-neighbouring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of POLR2A siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles leads to enhanced growth reduction of tumours characterized by hemizygous POLR2A loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise POLR2A targeted therapy in TNBC harbouring the common TP53 genomic alteration.
TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified POLR2A in the TP53-neighbouring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of POLR2A siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles leads to enhanced growth reduction of tumours characterized by hemizygous POLR2A loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise POLR2A targeted therapy in TNBC harbouring the common TP53 genomic alteration.Inhibiting POLR2A expression upon siRNA delivery represents a promising therapeutic strategy for triple negative breast cancers characterized by p53 inactivation.
TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified POLR2A in the TP53 -neighbouring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of POLR2A siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles leads to enhanced growth reduction of tumours characterized by hemizygous POLR2A loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise POLR2A targeted therapy in TNBC harbouring the common TP53 genomic alteration. Inhibiting POLR2A expression upon siRNA delivery represents a promising therapeutic strategy for triple negative breast cancers characterized by p53 inactivation.
TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified POLR2A in the TP53 -neighboring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of POLR2A siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles (siPol2@NPs) leads to enhanced growth reduction of tumours characterised by hemizygous POLR2A loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise POLR2A targeted therapy in TNBC harbouring the common TP53 genomic alteration.
Author Lu, Xiongbin
Liu, Sheng
Liu, Yunhua
Zhang, Yuntian
Stewart, Samantha
He, Xiaoming
Xu, Jiangsheng
Agarwal, Pranay
Van der Jeught, Kevin
Wan, Jun
Li, Yujing
Wang, Hai
Zhao, Gang
AuthorAffiliation 7. Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD 20742, USA
8. Marlene and Stewart Greenebaum Comprehensive Cancer Centre, University of Maryland, Baltimore, MD 21201, USA
4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
6. Department of Electronics Science and Technology, University of Science and Technology of China, Hefei, Anhui 230027, China
1. Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA
3. Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio 43210, USA
5. Melvin and Bren Simon Cancer Centre, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
2. Comprehensive Cancer Centre, The Ohio State University, Columbus, Ohio 43210, USA
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  email: shawnhe@umd.edu
  organization: Fischell Department of Bioengineering, University of Maryland, Comprehensive Cancer Centre, The Ohio State University, Department of Biomedical Engineering, The Ohio State University, Robert E. Fischell Institute for Biomedical Devices, University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Centre, University of Maryland
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ID FETCH-LOGICAL-c470t-3d1637c2873147d2322b31b134645b4584897ab8bb37de923b813d410fc371bd3
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ISSN 1748-3387
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IsDoiOpenAccess true
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Issue 4
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License Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
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Notes X.H. and X.L. conceived the project and supervised the study. X.H., X.L., J.X., and Y.L. designed experiments; J.X., Y.L. conducted experiments with assistance from Y.Li, H.W., KVDJ, P.A., S.L., and J.W.; X.H., X.L., J.X., Y.L., S.S., Y.Li, KVDJ, Y.Z., and G.Z. analysed data; J.X. and Y.L. wrote the manuscript draft; X.H., X.L., and S.S. edited the manuscript; and all authors approved the manuscript.
Authors contributions
ORCID 0000-0002-4626-2343
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Snippet TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are...
TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are...
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StartPage 388
SubjectTerms 631/61/350/354
631/61/54/152
639/925/352/2733
Animals
Bioavailability
Breast cancer
Cancer
Cell Line, Tumor
Cell Proliferation
Chemistry and Materials Science
DNA-Directed RNA Polymerases - metabolism
Endosomes - metabolism
Female
Gene Deletion
Humans
Hydrogen-Ion Concentration
Inactivation
Lysosomes - metabolism
Materials Science
Mice, Inbred C57BL
Mice, Nude
Nanoparticles
Nanoparticles - chemistry
Nanoparticles - ultrastructure
Nanotechnology
Nanotechnology and Microengineering
p53 Protein
pH effects
Ribonucleic acid
RNA
siRNA
Therapy
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - enzymology
Triple Negative Breast Neoplasms - pathology
Tumor Suppressor Protein p53 - metabolism
Tumors
Title Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer
URI https://link.springer.com/article/10.1038/s41565-019-0381-6
https://www.ncbi.nlm.nih.gov/pubmed/30804480
https://www.proquest.com/docview/2202773281
https://pubmed.ncbi.nlm.nih.gov/PMC6449187
Volume 14
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