CRISPR-Cas9 Screens Uncover NR2F2 as a Key Regulator of Endocrine Resistance in Breast Cancer

Estrogen receptor alpha (ERα) is a master regulator of transcription in healthy and cancerous mammary (breast) cells. Drugs or other exogenous agents that stimulate ER transcriptional activation have been shown to increase breast cancer risk, while inhibition of ER activity (via so-called endocrine therapy) is a very effective anti-cancer therapeutic strategy.

While a number of ER-inhibiting hormone therapies have been developed as systemic treatments for ER+ breast cancers, treatment resistance is a significant problem. This is often linked with somatic mutations including loss-of-function mutations in the gene encoding neurofibromin 1 (NF1). Exactly how NF1 loss promotes endocrine resistance remains poorly understood.

To probe the mechanisms underlying NF1 loss-induced endocrine resistance and identify potentially druggable targets to overcome this, researchers used CRISPR-Cas9 knockout screens in ER+ cells and carried out in vitro and in vivo studies using multiple ER+ cell line models, a xenograft mouse model of breast cancer and patient tumour-derived models.

The team, based at various institutes in the United States, Belgium and China, identified nuclear receptor subfamily 2 group F member 2 (NR2F2), as being critical for NF1 loss-induced endocrine resistance. They observed an induction of NR2F2 protein expression in ER+ cell line models and patient samples, and they propose that this occurs through activation of the mitogen-activated protein kinase (MAPK) pathway following NF1 loss or other genetic alterations in the MAPK pathway.

NR2F2 loss impaired NF1-knockout cell growth and restored the response to endocrine therapy, whereas NR2F2 overexpression conferred resistance across multiple models, suggesting a direct role for NR2F2 in modulating the ER response in breast cancer.

Therapeutically, the combination of NR2F2 targeting (through genetic disruption or small molecule inhibition) with endocrine therapy displayed potent anti-tumour activity in preclinical models, including patient-derived samples. Notably, NR2F2 inhibition showed broader applicability beyond NF1-mutant cancers, also overcoming resistance caused by loss of either of the tumour suppressor genes PTEN and ARID1A.

The authors highlight that targeting NR2F2 may offer advantages over current inhibitors for MAPK-altered cancers by potentially providing a more selective approach with reduced toxicities. They also suggest that targeting NR2F2 represents a promising strategy for developing "endocrine sensitisers" that could increase the clinical benefit of existing hormone therapies in ER+ breast cancers.

Read the open-access, Science Translational Medicine article entitled: 'Inhibition of NR2F2 restores hormone therapy response to endocrine refractory breast cancers' here.