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Genes Dev. 2017 Mar 15;31(6):553-566. doi: 10.1101/gad.292318.116.

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

Author information

1
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
2
Institute of Genetic Medicine, Newcastle University, Newcastle-Upon-Tyne NE1 3BZ, United Kingdom.
3
Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille 13009, France.
4
St. Jude Children's Research Hospital, Kay Research and Care Center, IA6053, Memphis, Tennessee 38105, USA.
5
Department of Systems Biology, Center for Computational Biology and Bioinformatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
6
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.

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.

KEYWORDS:

breast cancer; chemoresistance; microRNA; tumor suppressor

PMID:
28404630
PMCID:
PMC5393051
DOI:
10.1101/gad.292318.116
[Indexed for MEDLINE]
Free PMC Article

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