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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • October 22, 2019

Published In

Volume / Issue

  • 29 / 4

Start / End Page

  • 889 - 903.e10

PubMed ID

  • 31644911

Pubmed Central ID

  • PMC6874102

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2019.09.032


  • eng

Conference Location

  • United States