PPARs as determinants of the estrogen receptor lineage: use of synthetic lethality for the treatment of estrogen receptor-negative breast cancer

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.