Dataset Information

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.

SUBMITTER: Rodriguez-Barrueco R

PROVIDER: S-EPMC5393051 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Rodriguez-Barrueco Ruth R Nekritz Erin A EA Bertucci François F Yu Jiyang J Sanchez-Garcia Felix F Zeleke Tizita Z TZ Gorbatenko Andrej A Birnbaum Daniel D Ezhkova Elena E Cordon-Cardo Carlos C Finetti Pascal P Llobet-Navas David D Silva Jose M JM

Genes & development 20170301 6

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 ...[more]

PMID: 28404630

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Project description:BackgroundSkeletal muscle atrophy is a debilitating complication of many chronic diseases, disuse conditions, and ageing. Genome-wide gene expression analyses have identified that elevated levels of microRNAs encoded by the H19X locus are among the most significant changes in skeletal muscles in a wide scope of human cachectic conditions. We have previously reported that the H19X locus is important for the establishment of striated muscle fate during embryogenesis. However, the role of H19X-encoded microRNAs in regulating skeletal mass in adults is unknown.MethodsWe have created a transgenic mouse strain in which ectopic expression of miR-322/miR-503 is driven by the skeletal muscle-specific muscle creatine kinase promoter. We also used an H19X mutant mouse strain in which transcription from the locus is interrupted by a gene trap. Animal phenotypes were analysed by standard histological methods. Underlying mechanisms were explored by using transcriptome profiling and validated in the two animal models and cultured myotubes.ResultsOur results demonstrate that the levels of H19X microRNAs are inversely related to postnatal skeletal muscle growth. Targeted overexpression of miR-322/miR-503 impeded skeletal muscle growth. The weight of gastrocnemius muscles of transgenic mice was only 54.5% of the counterparts of wild-type littermates. By contrast, interruption of transcription from the H19X locus stimulates postnatal muscle growth by 14.4-14.9% and attenuates the loss of skeletal muscle mass in response to starvation by 12.8-21.0%. Impeded muscle growth was not caused by impaired IGF1/AKT/mTOR signalling or a hyperactive ubiquitin-proteasome system, instead accompanied by markedly dropped abundance of translation initiation factors in transgenic mice. miR-322/miR-503 directly targets eIF4E, eIF4G1, eIF4B, eIF2B5, and eIF3M.ConclusionsOur study illustrates a novel pathway wherein H19X microRNAs regulate skeletal muscle growth and atrophy through regulating the abundance of translation initiation factors, thereby protein synthesis. The study highlights how translation initiation factors lie at the crux of multiple signalling pathways that control skeletal muscle mass.

Dataset Information

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

Publications

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

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