Overcoming Endocrine Resistance by Targeting ER/FoxA1/IL 8 Axis
Abstract
Endocrine resistant (Endo-R) breast cancer (BC) challenges both patient care and basic research. 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 the 2nd year of this study, we determined the cause-and-effect of altered FOXA1/IL-8 expression on endocrine sensitivity across our multiple Endo-R cell models. Our major findings are: 1) FOXA1 overexpression decreases endocrine sensitivity and increases cell invasiveness in three ER+ BC cell models (MCF7L, ZR75-1, and 600MPE). 2) FOXA1 knockdown significantly decreases cell growth in all five Endo-R cell models and ER knockdown decreases cell growth only in resistant lines that maintain ER. IL-8 knockdown significantly inhibits cell growth in tamoxifen-resistant (TamR) vs. P cells of the MCF7L cell model. However, either IL-8 or the receptor CXCR1/2 neutralizing antibodies cannot inhibit Endo-R cell growth. 3) IL-8 knockdown partially rescues the endocrine sensitivity and reduces the cell invasion in MCF7L cells with FOXA1 overexpression. However, the cell growth that is inhibited by FOXA1 knockdown cannot be rescued by exogenous addition of IL-8 protein in culture medium. These data support the role of FOXA1/ER/IL-8 axis in promoting endocrine resistance and the downstream effector of IL-8 in mediating endocrine resistance and cell invasion induced by FOXA1 overexpression. Our data also suggest that the upregulation of IL-8 may involve an intracellular regulatory mechanism underlying the endocrine resistance regulated by high FOXA1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2016
- Accession Number
- AD1039664
Entities
People
- Agostina Nardone
- Anna Tsimelzon
- Carmine De Angelis
- Carolina Gutierrez
- Catherine S. Grasso
- Chad J Creighton
- Dean P. Edwards
- Delores Lopzz-terrada
- Emporia F. Hollingsworth
- Fugen Li
- Joe W. Gray
- Kent C Osborne
- Laura M Heiser
- Martin Shea
- Meghana V Trivedi
- Mothaffar F Rimawi
- Myles A. Brown
- Nicholas Wang
- Obi Griffith
- Paul Spellman
- Pavana Anur
- Rachel Schiff
- Resel Pereira
- Rinath Jeselsohn
- Shixia Huang
- Susan Hilsenbeck
- Xiaoyong Fu
Organizations
- Baylor College of Medicine