ERα-LBD, an isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance

Estrogen receptor alpha (ER alpha) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of an ER alpha isoform, ER alpha-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ER alpha-LBD is found to promote breast cancer growth and resistance to the ER alpha antagonist fulvestrant. ER alpha-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ER alpha-LBD expression and function does not appear to be restricted to cancers that express full length ER alpha but also promotes growth of triple-negative breast cancers and ER alpha-LBD transcript (ESR1-LBD) is also present in BC samples from both ER alpha(+) and ER alpha(-) human tumors. These findings point to ER alpha-LBD as a potential mediator of breast cancer progression and therapy resistance.