Overcoming Endocrine Resistance by Targeting ER/FoxA1/IL-8 Axis
Technical Report,30 Sep 2014,29 Sep 2015
Baylor College of Medicine Houston United States
- Hollingsworth,Emporia F.
- Creighton,Chad J.
- Heiser,Laura M.
- Hilsenbeck,Susan G.
- Gray,Joe W.
- Osborne,C. K.
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Endocrine resistant Endo-R breast cancer remains challenging for both clinical management and mechanistic understanding. We have developed and characterized a large panel of preclinical Endo-R cell models at multi-omics levels. Preliminary data revealed a novel ERFOXA1IL-8 axis as potential therapeutic targets to overcome endocrine resistance. In this 1st year funded study, we focused on the determination of this axis alteration in our Endo-R cell models and the investigation of the role of ERFOXA1 in IL-8 regulation in endocrine resistance. We further applied genome-wide FOXA1 ChIP-Seq and integrative analysis to understand the mechanistic role of increased FOXA1 in ligand-independent ER transcriptional reprogramming. Our major findings are 1 FOXA1 gene amplification exists in two independently developed MCF7-TamR models L and RN, but not in other Endo-R cell models 2 FOXA1 and IL-8 expression at either mRNA or protein levels was increased in multiple Endo-R cell models 3 FOXA1IL-8 up-regulation was also found in xenograft tumors resistant to endocrine therapy 4 FOXA1 or ER knockdown decreased the expression of IL-8 but not other cytokines in TamR cells 5 FOXA1 overexpression in P cells induced multiple cytokines including IL-8 expression in an ER-dependent manner, and a gene signature associated with cell migration and angiogenesis, and decreased response to estrogen 6 Cistromic profiling suggested the direct binding and regulation of IL-8 by ERFOXA1. These data substantiate the critical role of ERFOXA1IL-8 axis in endocrine resistance, and lay a solid foundation for further translational study in the following years.