VGLL1-directed TEAD activation drives endocrine therapy resistance in estrogen receptor positive breast cancer

Endocrine therapies are standard-of-care treatments for estrogen receptor (ER) positive breast cancer. However, patients with ER+ breast cancer develop resistance to these therapies and most relapsed patients die with endocrine-resistant metastatic disease. Here we show that resistance to the ER degrader, fulvestrant, is accompanied by epigenetic activation of the transcriptional co-activator VGLL1. Rewiring of the epigenome in therapy resistant cells also results in increased binding of the transcription factor TEAD4. Through interaction with TEAD4, VGLL1 induces the expression of genes implicated in cell proliferation in the resistant cells. We demonstrate that VGLL1 is necessary for the growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1/TEAD4 interaction blocked growth of fulvestrant-resistant cells, accompanied by inhibition of VGLL1/TEAD transcriptional programmes. Furthermore, we identify EGFR as an important downstream VGLL1 target, whereby VGLL1-directed EGFR upregulation sensitises fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, our findings identify VGLL1 as a key transcriptional driver in endocrine-resistant breast cancer and identify new therapeutic approaches for advanced breast cancer patients.