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Cell Rep. 2019 Oct 22;29(4):889-903.e10. doi: 10.1016/j.celrep.2019.09.032.

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

Author information

1
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
2
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA.
3
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
4
Viba Therapeutics, San Francisco, CA 94158, USA.
5
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
6
Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA 02139, USA.
7
Department of Biostatistics, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA.
8
Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
9
The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
10
Breast Cancer Now, Toby Robins Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
11
Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, SW3 6JJ, UK.
12
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
13
Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
14
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: donald.mcdonnell@duke.edu.

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.

KEYWORDS:

FOXA1; GRHL2; LYPD3; breast cancer; chromatin; cistrome; enhancer; histone; tamoxifen

PMID:
31644911
DOI:
10.1016/j.celrep.2019.09.032
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