Carcinogenesis. 2013 Aug;34(8):1889-99.

MicroRNA-191, an estrogen-responsive microRNA, functions as an oncogenic regulator in human breast cancer.

Nagpal N, Ahmad HM, Molparia B, Kulshreshtha R.

Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, New Delhi, India.

 

ABSTRACT:

Estrogen and microRNA mediated gene regulation play a crucial role in breast cancer biology. However, a functional link between the two major players remains unclear. The work here reveals miR-191 as an estrogen inducible oncomiR in breast cancer that promotes several hallmarks of cancer including enhanced cell proliferation, migration, chemoresistance and survival in tumor microenvironment. miR-191 is a direct ER target and our results suggest existence of a positive regulatory feedback loop. We show miR-191 as critical mediator of estrogen mediated cell proliferation. Investigations of mechanistic details of miR-191 functions identify several cancer related genes like BDNF, CDK6 and SATB1 as miR-191 targets. miR-191 and SATB1 show inverse correlation of expression. miR-191 mediated enhanced cell proliferation and migration is partly dependent on targeted downregulation of SATB1. Further, functional validation of estrogen:miR-191:SATB1 link suggests a cascade initiated by estrogen that induces miR-191 in ER dependent manner to target SATB1, a global chromatin remodeler, thereby contributing to estrogen specific gene signature to regulate genes like ANXA1, PIWIL2, CASP4, ESR1/ESR2, PLAC1 and SOCS2 involved in breast cancer progression and migration. Overall, the identification of estrogen/ER/miR-191/SATB1 cascade seems to be a significant pathway in estrogen signaling in breast cancer with miR-191 as oncogenic player.

PMID: 23542418

 

SUPPLEMENT:

Breast cancer is second most common cancer in women. About 70% of these are hormone dependent the pathogenesis of which is highly dependent on a hormone called estrogen. This laid basis for the anti-estrogen therapies that are regularly given for the control of this disease. However, in several instances the therapies fail due to acquired resistance leading to more aggressive phenotype and poor prognosis. This could be due to lacuna in our understanding of the mechanism of estrogen action.

Estrogen works by activating a specific set of genes to mediate its functions. However, recently a class of small non-coding RNAs called microRNAs has been discovered to be regulated by estrogen through ER. While functional relevance of estrogen impact on protein coding genes is well understood its relationship with these small new entrants as part of its transcriptome remains mysterious. Considering nature of miRNA action as posttranscriptional regulators and increasing list of miRNAs been discovered as oncomiRs or tumor suppressors it becomes imperative to identify miRNAs that act as critical mediators of estrogen action. The identification of these molecules may help not only in elucidating estrogen:microRNA:gene:function network but may also help in identification of novel targets for hormone dependent breast cancer therapy.

Through literature search we identified microRNA, miR-191 that was shown to be present at very high levels in several different cancer patients including breast cancer patients. More intriguing was the fact that ER+ patients showed much higher levels as compared to the ER- patients. Thus, we sought to find out the reason for this observation and the functional relevance of the same. Our studies showed that estrogen on binding to ER brings about induction of miR-191 in a time dependent manner. Functional studies revealed miR-191 to be a very notorious microRNA in the sense that not only it promoted cancer cell proliferation and survival but also provided increased resistance to various therapies (chemical drug and radiation). In addition, overexpression of miR-191 promoted cell migration/invasion and thus promotes metastasis. Several cancer related genes like BDNF, BCL11A, SATB1 and CDK6 were found to be part of miR-191 signaling network. Further, functional analysis and experimentation to establish the link between miR-191 & SATB1 (a known chromatin remodeler) revealed that targeted downregulation of SATB1 by miR-191 is necessary to mediate miR-191 effects on cell proliferation & migration.

All the above studies strongly suggest miR-191 to be an attractive target for breast cancer therapy. However, all the work was done using ER+ cell lines. When similar studies were done with ER- cells, it turned out that miR-191 rather worked as a tumor suppressor, overexpression of which inhibits breast cancer cell proliferation. Thus, miR-191 based therapy warrants discrete treatment plans based on patient ER status. While ER+ patients may benefit from miR-191 inhibition, ER- patients need to be treated with miR-191 mimics.

Taken together, through our work here we identified miR-191 as an important mediator of estrogen signaling in promoting the aggressive phenotype of ER responsive breast cancer. Based on our studies anti-miR-191 therapy may prove useful for treatment of hormone receptor positive breast cancer.

Ritu, Kulshreshtha Figure-1

Reference:

Neha Nagpal et al. MicroRNA-191, an estrogen-responsive microRNA, functions as an oncogenic regulator in human breast cancer. Carcinogenesis (2013) 34 (8): 1889-1899 doi:10.1093/carcin/bgt107.

By permission of Oxford University Press.

http://carcin.oxfordjournals.org/content/34/8/1889.full.pdf+html.

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