Inhibition of NR2F2 restores hormone therapy response to endocrine refractory breast cancers

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Endocrine resistance is a major challenge in estrogen receptor-positive (ER+) breast cancer treatment.
• Somatic mutations, like neurofibromin 1 (NF1) loss, contribute to endocrine resistance, but underlying mechanisms remain unclear.
• Understanding these mechanisms is crucial for developing effective endocrine therapies.

Purpose of the Study:

• To elucidate the mechanisms by which NF1 loss induces endocrine resistance in ER+ breast cancer.
• To identify novel therapeutic targets for overcoming endocrine resistance.

Main Methods:

• CRISPR-Cas9 knockout screens were employed to identify genes essential for NF1 loss-induced endocrine resistance.
• Mechanistic studies involved analyzing the role of nuclear receptor subfamily 2 group F member 2 (NR2F2) in regulating the estrogen receptor (ER) transcriptional program.
• Experiments included cell line models, patient-derived xenografts, and organoid-based xenografts.

Main Results:

• CRISPR-Cas9 screens identified NR2F2 as essential for NF1 loss-induced endocrine resistance.
• NF1 loss activates the mitogen-activated protein kinase (MAPK) pathway, leading to NR2F2 induction.
• Increased NR2F2 represses ER transcriptional programs by altering ER cistrome, coregulator balance, and chromatin accessibility.
• NR2F2 depletion or inhibition restored sensitivity to hormone therapies in models with various resistance mechanisms (NF1, ARID1A, PTEN loss, KRAS overexpression).

Conclusions:

• NR2F2 is a critical mediator of endocrine resistance in ER+ breast cancer, driven by MAPK pathway activation.
• NR2F2 inhibition represents a promising therapeutic strategy to overcome diverse endocrine resistance mechanisms.
• Targeting NR2F2 could enhance the efficacy of endocrine treatments for breast cancer patients.