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

TitleERα-LBD, an isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance.
Publication TypeJournal Article
Year of Publication2022
AuthorsStrillacci A, Sansone P, Rajasekhar VK, Turkekul M, Boyko V, Meng F, Houck-Loomis B, Brown D, Berger MF, Hendrickson RC, Chang Q, de Stanchina E, Pareja F, Reis-Filho JS, Rajappachetty RSegu, Del Priore I, Liu B, Cai Y, Penson A, Mastroleo C, Berishaj M, Borsetti F, Spisni E, Lyden D, Chandarlapaty S, Bromberg J
JournalNPJ Breast Cancer
Date Published2022 Aug 23

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.

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Alternate JournalNPJ Breast Cancer
PubMed ID35999225
PubMed Central IDPMC9399095
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 CA234361 / CA / NCI NIH HHS / United States
R01 CA245069 / CA / NCI NIH HHS / United States

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