ERα-LBD, an isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance
Year: 2022
Type: article
Abstract: Estrogen receptor alpha (ERα) 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 ERα isoform, ERα-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ERα-LBD is found to promote breast cancer growth and resistance to the ERα antagonist fulvestrant. ERα-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ERα-LBD expression and function does not appear to be restricted to cancers that express full length ERα but also promotes growth of triple-negative breast cancers and ERα-LBD transcript (ESR1-LBD) is also present in BC samples from both ERα(+) and ERα(-) human tumors. These findings point to ERα-LBD as a potential mediator of breast cancer progression and therapy resistance.
Source: npj Breast Cancer
Authors: Antonio Strillacci, Pasquale Sansone, Vinagolu K. Rajasekhar, Mesruh Turkekul, Vitaly Boyko, Fanli Meng, Brian Houck-Loomis, David Brown, Michael F. Berger, Ronald C. Hendrickson, Qing Chang, Elisa de Stanchina, Fresia Pareja, Jorge S. Reis-Filho, Ramya Segu Rajappachetty, Isabella Del Priore, Bo Liu, Yanyan Cai, Alex Penson, Chiara Mastroleo, Marjan Berishaj, Francesca Borsetti, Enzo Spisni, David Lyden, Sarat Chandarlapaty, Jacqueline Bromberg
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,390
Awards: G289723095, G3294690985, G3343554601, G5047892322, Therapeutic approaches to ER mutant breast cancer, LTQ-ORBITRAP VELOS Tandem Mass Spectrometer, Defining the impact of mutant oncogene zygosity, G782458776, MSK SPORE in Genomic Instability in Breast Cancer, G9000142645, Cancer Center Support Grant
OpenAlex ID: W4292707925