Resistance to endocrine therapies (ET) is common in estrogen receptor (ER)
positive breast cancer, and most relapsed patients die with ET-resistant disease.
While genetic mutations provide explanations for some relapses, mechanisms of
resistance remain undefined in many cases. Drug-induced epigenetic
reprogramming has been shown to provide possible routes to resistance. By
analyzing histone H3 lysine 27 acetylation (H3K27ac) profiles and transcriptional
reprogramming in models of ET resistance, we discovered that selective ER
degraders (SERDs), such as fulvestrant, promote expression of VGLL1, a co activator for TEAD transcription factors. VGLL1, acting via TEADs, promoted
expression of genes that drive growth of fulvestrant-resistant breast cancer cells.
Pharmacological disruption of VGLL1/TEAD4 interaction inhibited VGLL1/TEAD induced transcriptional programs to prevent growth of resistant cells. EGFR was
among the VGLL1/TEAD-regulated genes, and VGLL1-directed EGFR upregulation
sensitized fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken
together, these findings identify VGLL1 as a transcriptional driver in ET resistance
and advance therapeutic possibilities for relapsed ER+ breast cancer patients.