The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.

Abstract

Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins.

• Authors: Kimberly J Cocce, Jeff S Jasper, Taylor K Desautels, Logan Everett, Suzanne Wardell, Thomas Westerling, Robert Baldi, Tricia M Wright, Kendall Tavares, Alex Yllanes, Yeeun Bae, Jeremy T Blitzer, Craig Logsdon, Daniel P Rakiec, David A Ruddy, Tiancong Jiang, Gloria Broadwater, Terry Hyslop, Allison Hall, Muriel Laine, Linda Phung, Geoffrey L Greene, Lesley-Ann Martin, Sunil Pancholi, Mitch Dowsett, Simone Detre, Jeffrey R Marks, Gregory E Crawford, Myles Brown, John D Norris, Ching-Yi Chang, Donald P McDonnell
• Journal: Cell reports (Cell Rep) Vol. 29 Issue 4 Pg. 889-903.e10 (10 22 2019) ISSN: 2211-1247 [Electronic] United States
• PMID: 31644911 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Agr2 protein, mouse
• Antibodies, Neutralizing
• Cell Adhesion Molecules
• Estrogen Receptor alpha
• Foxa1 protein, mouse
• GPI-Linked Proteins
• Hepatocyte Nuclear Factor 3-alpha
• LYPD3 protein, mouse
• Mucoproteins
• Oncogene Proteins
• Transcription Factors
• grainy head-like 2 protein, mouse

Topics

• Animals
• Antibodies, Neutralizing (immunology, therapeutic use)
• Cell Adhesion Molecules (immunology, metabolism)
• Drug Resistance, Neoplasm
• Estrogen Receptor alpha (genetics)
• Female
• GPI-Linked Proteins (immunology, metabolism)
• Hepatocyte Nuclear Factor 3-alpha (metabolism)
• Humans
• MCF-7 Cells
• Mammary Neoplasms, Experimental (drug therapy, genetics, metabolism)
• Mice
• Mucoproteins (immunology, metabolism)
• Oncogene Proteins (immunology, metabolism)
• Transcription Factors (metabolism)