Accession Number : AD1004019


Title :   Overcoming Endocrine Resistance by Targeting ER/FoxA1/IL-8 Axis


Descriptive Note : Technical Report,30 Sep 2014,29 Sep 2015


Corporate Author : Baylor College of Medicine Houston United States


Personal Author(s) : Fu,Xiaoyong ; Jeselsohn,Rinath ; Pereira,Resel ; Hollingsworth,Emporia F ; Creighton,Chad J ; Li,Fugen ; Shea,Martin ; Nardone,Agostina ; Wang,Tao ; Heiser,Laura M ; Anur,Pavana ; Wang,Nicholas ; Grasso,Catie ; Spellman,Paul ; Gutierrez,Carolina ; Lopez-Terrada,Dolores ; Hilsenbeck,Susan G ; Gray,Joe W ; Brown,Myles ; Osborne,C K


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1004019.pdf


Report Date : 01 Oct 2015


Pagination or Media Count : 47


Abstract : 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 ER/FOXA1/IL-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 ER/FOXA1 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) FOXA1/IL-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 ER/FOXA1. These data substantiate the critical role of ER/FOXA1/IL-8 axis in endocrine resistance, and lay a solid foundation for further translational study in the following years.


Descriptors :   estrogens , cytokines , RESISTANCE(BIOLOGY) , breast cancer , cells(biology) , neoplasms


Distribution Statement : APPROVED FOR PUBLIC RELEASE