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The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine
Kimberly J Cocce1, Jeff S Jasper1, Taylor K Desautels1
1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
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.
Insights
Endocrine therapy resistance in ERα-positive breast cancer is common. Researchers identified a new pathway involving FOXA1, GRHL2, LYPD3, and AGR2, and blocking this pathway with antibodies stopped resistant tumor growth in mice.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Endocrine therapies are crucial for estrogen receptor-alpha (ERα)-positive breast cancer.
- De novo and acquired resistance to these therapies limit their clinical effectiveness.
- Identifying new therapeutic targets is essential to overcome resistance.
Purpose of the Study:
- To identify and exploit targetable vulnerabilities in endocrine therapy-resistant breast cancer.
- To elucidate a novel molecular pathway driving resistance.
- To evaluate therapeutic strategies targeting this pathway.
Main Methods:
- Utilized cellular and mouse models of endocrine therapy-sensitive and resistant breast cancer.
- Employed contemporary discovery platforms to identify key molecular players.
- Investigated the roles of transcription factors FOXA1 and GRHL2, and their downstream targets.
- Assessed the efficacy of blocking antibodies against LYPD3 and AGR2 in preclinical models.
Main Results:
- Identified a resistance pathway comprising FOXA1, GRHL2, LYPD3, and AGR2.
- Demonstrated that LYPD3 and AGR2 are coregulated targets within this pathway.
- Showed that blocking antibodies against LYPD3 or AGR2 inhibit the growth of resistant tumors in mice.
Conclusions:
- The identified FOXA1/GRHL2/LYPD3/AGR2 pathway represents a targetable vulnerability in endocrine therapy-resistant breast cancer.
- Inhibition of LYPD3 or AGR2 shows promise for treating resistant disease.
- These findings provide a strong rationale for the clinical development of humanized antibodies targeting LYPD3 or AGR2.
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