Overcoming Endocrine Resistance by Targeting ER/FoxA1/IL-8 Axis
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1004019
Entities
People
- Agostina Nardone
- C. K. Osborne
- Carolina Gutierrez
- Catie Grasso
- Chad J Creighton
- Dolores Lopez-terrada
- Emporia F. Hollingsworth
- Fugen Li
- Joe W. Gray
- Laura M Heiser
- Martin Shea
- Myles A. Brown
- Nicholas Wang
- Paul Spellman
- Pavana Anur
- Resel Pereira
- Rinath Jeselsohn
- Susan Hilsenbeck
- Tao Wang
- Xiaoyong Fu
Organizations
- Baylor College of Medicine