ISY-24-3 - ESR1 gene alterations related to endocrine resistance in metastatic breast cancer

Abstract

Estrogen receptor (ER) positive breast cancer can be treated by endocrine therapy; however a certain population of ER-positive patients becomes resistant to endocrine therapies. Expression of the ESR1 gene encoding ER was upregulated in response to estrogen deprivation (LTED cells), which was usually seen in the metastatic breast cancer (MBC) with resistance to aromatase inhibitor. We found that RNAs from ESR1 gene locus were induced both from coding and non-coding regions in LTED cells using both total RNA-sequencing and mRNA-seq analyses. We termed these RNAs as Eleanors (ESR1 locus enhancing and activating non-coding RNAs). Depletion of one of Eleanors, upstream (u)-Eleanor, impaired cell growth and transcription of intragenic Eleanors and ESR1 mRNA, indicating that Eleanors cis-activate the ESR1 gene. The activation of the ESR1 gene locus by the Eleanors is critical for cancer cell adaptation to estrogen deprivation and can be a new therapeutic and diagnostic targets in endocrine therapy resistance. Recent evidences have shown that the key potential mechanisms of the resistance to aromatase inhibitors based therapy involve identifying activating mutations affecting the ligand-binding domain of the ESR1 gene. We initially developed a droplet digital PCR-based method for the sensitive detection of ESR1 mutations, Y537S, Y537N, Y537C, and D538G, which showed ESR1 mutations occurred in 2.5% of primary breast cancer specimens (n = 270) and in 20% of MBC specimens (n = 55). Furthermore, the patients with ESR1 mutations from cell free (plasma) DNA tended to have a poorer response to post-treatment, compared with wild-type patients. Taken together, ESR1 gene alterations including non-coding RNA are profoundly related to the endocrine resistance in metastatic breast cancer and could be a predictor of the usage to combination with the signal transduction inhibitor, such as mTOR inhibitor, PI3K inhibitor.