PPARs as determinants of the estrogen receptor lineage: use of synthetic lethality for the treatment of estrogen receptor-negative breast cancer
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Robert I. Glazer1 and Levy Kopelovich2
1 Department of Oncology, Georgetown University School of Medicine, and Lombardi Comprehensive Cancer Center, NW, Washington, D.C., USA
2 Department of Medicine, Weill Cornell College of Medicine, New York, NY, USA
Robert I. Glazer, email:
Keywords: PPARδ, PPARγ, ER
Received: December 05, 2016 Accepted: March 02, 2017 Published: April 20, 2017
The Dilemma: Estrogen receptora-negative (ER-) breast cancer lacks a specific critical target to control tumor progression.
The Objective: To identify mechanisms that enable increased expression of the ER+ lineage in an otherwise ER- breast cancer.
Preface: The nuclear receptor superfamily members PPARγ and PPARδ regulate gene expression associated with a multitude of pathways, including intermediary metabolism, angiogenesis, proliferation and inflammation (see reviews [1-3]). Recent developments using transgenic and knockout mice, as well as pharmacologic intervention with PPARγ and PPARδ agonists, have revealed a previously unknown relationship between PPARγ suppression and PPARδ activation that leads to the appearance of ER+ tumors, enabling a synthetic lethality approach by anti-ER therapy. The ability to selectively affect the ER+ lineage by modulating PPARγ and PPARδ activity represents a new clinical paradigm and opportunity to treat ER- cancer with PPARγ and PPARδ modulating agents, ultimately rendering them more responsive to adjuvant therapy.
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