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G-Quadruplexes as Sensing Probes
Molecules 2013, 18(12), 15019-15034; doi:10.3390/molecules181215019

Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics

1 College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA 2 Department of Pharmacology, School of Pharmacy, The University of Mississippi, University, MS 38677, USA
* Author to whom correspondence should be addressed.
Received: 25 September 2013 / Revised: 25 November 2013 / Accepted: 26 November 2013 / Published: 5 December 2013
(This article belongs to the Special Issue G-Quadruplexes & i-Motif DNA)
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ADAM-15, with known zymogen, secretase, and disintegrin activities, is a catalytically active member of the ADAM family normally expressed in early embryonic development and aberrantly expressed in various cancers, including breast, prostate and lung. ADAM-15 promotes extracellular shedding of E-cadherin, a soluble ligand for the HER2/neu receptor, leading to activation, increased motility, and proliferation. Targeted downregulation of both ADAM-15 and HER2/neu function synergistically kills breast cancer cells, but to date there are no therapeutic options for decreasing ADAM-15 function or expression. In this vein, we have examined a unique string of guanine-rich DNA within the critical core promoter of ADAM-15. This region of DNA consists of seven contiguous runs of three or more consecutive guanines, which, under superhelical stress, can relax from duplex DNA to form an intrastrand secondary G-quadruplex (G4) structure. Using biophysical and biological techniques, we have examined the G4 formation within the entire and various truncated regions of the ADAM-15 promoter, and demonstrate strong intrastrand G4 formation serving to function as a biological silencer element. Characterization of the predominant G4 species formed within the ADAM-15 promoter will allow for specific drug targeting and stabilization, and the further development of novel, targeted therapeutics.
Keywords: G-quadruplex; ADAM-15; breast cancer G-quadruplex; ADAM-15; breast cancer
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Brown, R.V.; Gaerig, V.C.; Simmons, T.; Brooks, T.A. Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics. Molecules 2013, 18, 15019-15034.

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