The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.
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Date
2019-10-22ICR Author
Author
Cocce, KJ
Jasper, JS
Desautels, TK
Everett, L
Wardell, S
Westerling, T
Baldi, R
Wright, TM
Tavares, K
Yllanes, A
Bae, Y
Blitzer, JT
Logsdon, C
Rakiec, DP
Ruddy, DA
Jiang, T
Broadwater, G
Hyslop, T
Hall, A
Laine, M
Phung, L
Greene, GL
Martin, L-A
Pancholi, S
Dowsett, M
Detre, S
Marks, JR
Crawford, GE
Brown, M
Norris, JD
Chang, C-Y
McDonnell, DP
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Humans
Mice
Mammary Neoplasms, Experimental
Cell Adhesion Molecules
Mucoproteins
Oncogene Proteins
Estrogen Receptor alpha
Transcription Factors
Drug Resistance, Neoplasm
Female
Hepatocyte Nuclear Factor 3-alpha
Antibodies, Neutralizing
GPI-Linked Proteins
MCF-7 Cells
Research team
Endocrinology
Language
eng
Date accepted
2019-09-12
License start date
2019-10
Citation
Cell reports, 2019, 29 (4), pp. 889 - 903.e10
Publisher
CELL PRESS