Oncotarget

Research Papers:

DVL1 and DVL3 differentially localize to CYP19A1 promoters and regulate aromatase mRNA in breast cancer cells

Isabel Castro-Piedras, Monica Sharma, Meghan den Bakker, Deborah Molehin, Edgar G. Martinez, David Vartak, Wendy M. Pruitt, Jena Deitrick, Sharilyn Almodovar and Kevin Pruitt _

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Oncotarget. 2018; 9:35639-35654. https://doi.org/10.18632/oncotarget.26257

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Abstract

Isabel Castro-Piedras1,*, Monica Sharma1,*, Meghan den Bakker1, Deborah Molehin1, Edgar G. Martinez1, David Vartak1, Wendy M. Pruitt1, Jena Deitrick1, Sharilyn Almodovar1 and Kevin Pruitt1

1Department of Immunology & Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA

*These authors have equally contributed to this work

Correspondence to:

Kevin Pruitt, email: kevin.pruitt@ttuhsc.edu

Keywords: aromatase; CYP19A1; dishevelled; DVL; breast cancer

Received: August 19, 2018     Accepted: October 06, 2018     Published: November 02, 2018

ABSTRACT

The CYP19A1 gene encodes aromatase, an enzyme that converts androgens into estrogens and consequently directly contributes to both the depletion of androgens and the synthesis of estrogens in several organs. Aromatase is critical for diverse biological processes such as proliferation, regulation of fat metabolism and hormone signaling. Additionally, it is also overexpressed in diverse cancers and drives hormone-dependent tumor progression and increases 17-β-estradiol (E2) within tumors and the tumor microenvironment. Although the inhibition of E2 production via aromatase inhibitors represents a major therapeutic paradigm in clinical oncology, fundamental questions regarding how cancer cells gain the capacity to overexpress aromatase remain unanswered. Multiple tissue-specific CYP19A1 promoters are known to be aberrantly active in tumors, yet how this occurs is unclear. Here, for the first time, we report that Dishevelled (DVL) proteins, which are key mediators of Wnt signaling, regulate aromatase expression in multiple breast cancer cell lines. We also report that DVL enters the nucleus and localizes to at least two different CYP19A1 promoters (pII and I.4) previously reported to drive overexpression in breast tumors and to a very distal CYP19A1 placental promoter (I.1) that remains poorly characterized. We go on to demonstrate that DVL-1 and DVL-3 loss of function leads to differential changes in various aromatase transcripts and in E2 production. The report, herein, uncovers a new regulator of CYP19A1 transcription and for the first time demonstrates that DVL, a critical mediator of WNT signaling, contributes to aberrant breast cancer-associated estrogen production.


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