The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer
Year: 2019
Type: article
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.
Source: Cell Reports
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
Institutions: Duke University, Duke Medical Center, North Carolina State University, Harvard University, Dana-Farber Cancer Institute, The University of Texas MD Anderson Cancer Center, Duke Cancer Institute, University of Chicago, Institute of Cancer Research, Breast Cancer Now, Royal Marsden NHS Foundation Trust, Royal Marsden Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: Novartis, Center for Outcomes Research and Evaluation, Yale School of Medicine, Duke University, Israel National Road Safety Authority, Susan G. Komen, Royal Marsden NHS Foundation Trust, National Institutes of Health, Manchester Biomedical Research Centre, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W2982007450