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miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy.

Abstract The female mammary gland is a very dynamic organ that undergoes continuous tissue remodeling during adulthood. Although it is well established that the number of menstrual cycles and pregnancy (in this case transiently) increase the risk of breast cancer, the reasons are unclear. Growing clinical and experimental evidence indicates that improper involution plays a role in the development of this malignancy. Recently, we described the miR-424(322)/503 cluster as an important regulator of mammary epithelial involution after pregnancy. Here, through the analysis of ∼3000 primary tumors, we show that miR-424(322)/503 is commonly lost in a subset of aggressive breast cancers and describe the genetic aberrations that inactivate its expression. Furthermore, through the use of a knockout mouse model, we demonstrate for the first time that loss of miR-424(322)/503 promotes breast tumorigenesis in vivo. Remarkably, we found that loss of miR-424(322)/503 promotes chemoresistance due to the up-regulation of two of its targets: BCL-2 and insulin-like growth factor-1 receptor (IGF1R). Importantly, targeted therapies blocking the aberrant activity of these targets restore sensitivity to chemotherapy. Overall, our studies reveal miR-424(322)/503 as a tumor suppressor in breast cancer and provide a link between mammary epithelial involution, tumorigenesis, and the phenomenon of chemoresistance.
PMID
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Authors

Mayor MeshTerms
Keywords

breast cancer

chemoresistance

microRNA

tumor suppressor

Journal Title genes & development
Publication Year Start




PMID- 28404630
OWN - NLM
STAT- MEDLINE
DA  - 20170413
DCOM- 20170418
LR  - 20170418
IS  - 1549-5477 (Electronic)
IS  - 0890-9369 (Linking)
VI  - 31
IP  - 6
DP  - 2017 Mar 15
TI  - miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes
      resistance to chemotherapy.
PG  - 553-566
LID - 10.1101/gad.292318.116 [doi]
AB  - The female mammary gland is a very dynamic organ that undergoes continuous tissue
      remodeling during adulthood. Although it is well established that the number of
      menstrual cycles and pregnancy (in this case transiently) increase the risk of
      breast cancer, the reasons are unclear. Growing clinical and experimental
      evidence indicates that improper involution plays a role in the development of
      this malignancy. Recently, we described the miR-424(322)/503 cluster as an
      important regulator of mammary epithelial involution after pregnancy. Here,
      through the analysis of approximately 3000 primary tumors, we show that
      miR-424(322)/503 is commonly lost in a subset of aggressive breast cancers and
      describe the genetic aberrations that inactivate its expression. Furthermore,
      through the use of a knockout mouse model, we demonstrate for the first time that
      loss of miR-424(322)/503 promotes breast tumorigenesis in vivo. Remarkably, we
      found that loss of miR-424(322)/503 promotes chemoresistance due to the
      up-regulation of two of its targets: BCL-2 and insulin-like growth factor-1
      receptor (IGF1R). Importantly, targeted therapies blocking the aberrant activity 
      of these targets restore sensitivity to chemotherapy. Overall, our studies reveal
      miR-424(322)/503 as a tumor suppressor in breast cancer and provide a link
      between mammary epithelial involution, tumorigenesis, and the phenomenon of
      chemoresistance.
CI  - (c) 2017 Rodriguez-Barrueco et al.; Published by Cold Spring Harbor Laboratory
      Press.
FAU - Rodriguez-Barrueco, Ruth
AU  - Rodriguez-Barrueco R
AD  - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New
      York 10029, USA.
AD  - Institute of Genetic Medicine, Newcastle University, Newcastle-Upon-Tyne NE1 3BZ,
      United Kingdom.
FAU - Nekritz, Erin A
AU  - Nekritz EA
AD  - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New
      York 10029, USA.
FAU - Bertucci, Francois
AU  - Bertucci F
AD  - Centre de Recherche en Cancerologie de Marseille, Institut Paoli-Calmettes,
      Aix-Marseille Universite, Marseille 13009, France.
FAU - Yu, Jiyang
AU  - Yu J
AD  - St. Jude Children's Research Hospital, Kay Research and Care Center, IA6053,
      Memphis, Tennessee 38105, USA.
FAU - Sanchez-Garcia, Felix
AU  - Sanchez-Garcia F
AD  - Department of Systems Biology, Center for Computational Biology and
      Bioinformatics, Herbert Irving Comprehensive Cancer Center, Columbia University, 
      New York, New York 10032, USA.
FAU - Zeleke, Tizita Z
AU  - Zeleke TZ
AD  - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New
      York 10029, USA.
FAU - Gorbatenko, Andrej
AU  - Gorbatenko A
AD  - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New
      York 10029, USA.
FAU - Birnbaum, Daniel
AU  - Birnbaum D
AD  - Centre de Recherche en Cancerologie de Marseille, Institut Paoli-Calmettes,
      Aix-Marseille Universite, Marseille 13009, France.
FAU - Ezhkova, Elena
AU  - Ezhkova E
AD  - Department of Cell, Developmental, and Regenerative Biology, Black Family Stem
      Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York
      10029, USA.
FAU - Cordon-Cardo, Carlos
AU  - Cordon-Cardo C
AD  - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New
      York 10029, USA.
FAU - Finetti, Pascal
AU  - Finetti P
AD  - Centre de Recherche en Cancerologie de Marseille, Institut Paoli-Calmettes,
      Aix-Marseille Universite, Marseille 13009, France.
FAU - Llobet-Navas, David
AU  - Llobet-Navas D
AD  - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New
      York 10029, USA.
AD  - Institute of Genetic Medicine, Newcastle University, Newcastle-Upon-Tyne NE1 3BZ,
      United Kingdom.
FAU - Silva, Jose M
AU  - Silva JM
AD  - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New
      York 10029, USA.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
RN  - 0 (IGF1R protein, human)
RN  - 0 (MIRN424 microRNA, mouse)
RN  - 0 (MIRN424 microrna, human)
RN  - 0 (MIRN503 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn503 microRNA, mouse)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Receptors, Somatomedin)
RN  - EC 3.1.3.48 (cdc25 Phosphatases)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/drug therapy/*genetics/mortality
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Gene Deletion
MH  - Genes, Tumor Suppressor
MH  - Humans
MH  - Mammary Neoplasms, Experimental/genetics
MH  - Mice
MH  - MicroRNAs/*genetics
MH  - Pregnancy
MH  - Pregnancy Complications, Neoplastic/genetics
MH  - Proto-Oncogene Proteins c-bcl-2/genetics
MH  - Receptors, Somatomedin/genetics
MH  - cdc25 Phosphatases/genetics
OTO - NOTNLM
OT  - breast cancer
OT  - chemoresistance
OT  - microRNA
OT  - tumor suppressor
EDAT- 2017/04/14 06:00
MHDA- 2017/04/19 06:00
CRDT- 2017/04/14 06:00
PHST- 2016/10/18 [received]
PHST- 2017/03/06 [accepted]
AID - 31/6/553 [pii]
AID - 10.1101/gad.292318.116 [doi]
PST - ppublish
SO  - Genes Dev. 2017 Mar 15;31(6):553-566. doi: 10.1101/gad.292318.116.

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