eprintid: 35898
rev_number: 14
eprint_status: archive
userid: 8695
dir: disk0/00/03/58/98
datestamp: 2025-01-14 14:55:04
lastmod: 2025-01-16 13:54:21
status_changed: 2025-01-14 14:55:04
type: doctoralThesis
metadata_visibility: show
creators_name: Müller, Janina
title: GLYATL1, a Novel Player in Endocrine Therapy Resistance in 
Breast Cancer
subjects: ddc-570
divisions: i-140001
adv_faculty: af-14
abstract: Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer-related death in females. The most prevalent breast cancer subtype, luminal A, is characterized by high expression and activity of the estrogen receptor (ER). These luminal A patients typically have a favorable prognosis due to the availability of endocrine therapies targeting the estrogen receptor, like tamoxifen and fulvestrant, or by inhibiting aromatase, a critical enzyme in estrogen synthesis. However, 40- 50% of ER-positive breast cancers with late-stage disease either fail to respond to this therapeutic approach or relapse as a consequence of de-novo or acquired endocrine therapy resistance.
This study focuses on characterizing GLYATL1 (glutamine-N-acyltransferase), a gene previously found to be highly upregulated in aromatase inhibitor-resistant luminal A breast cancer cell lines. In these cell lines, I observed that GLYATL1 expression is inversely correlated with estrogen supply and is regulated by the luminal transcription factors FOXA1 and ESR1 under estrogen-depleted conditions. While GLYATL1 overexpression alone was insufficient to induce a resistant phenotype, knockdown, and knockout partially re-sensitize resistant cells to antiestrogen treatment.
Despite the distinct mitochondrial localization of GLYATL1 and the enzymatic ability to transfer acyl groups to glutamine, I could not identify a specific acyl donor or metabolic pathway alterations influenced by GLYATL1. However, I could observe that GLYATL1 promoted succinate accumulation and contributed to maintaining low oxidative stress levels in the resistant cells. These alterations could lead to several biological changes such as pathway deregulation and epigenetic reprogramming.
In the GLYATL1 knockout cell lines, I could observe significant upregulation of p53 and the JAK-STAT signaling pathway, along with downregulation of the TGFβ and key cell cycle regulator pathways. In contrast, these pathways were partially inversely activated in the resistant cells compared to wildtype cells. Furthermore, I could observe a significant influence of GLYATL1 on the epigenetic landscape, specifically on H3K27 acetylation and dimethylation, H3K4 trimethylation, and H3K64 acetylation histone modifications.
These findings highlight a novel role of GLYATL1 in the context of endocrine thera-py resistance in ER-positive breast cancer by potentially impacting succinate accu-mulation, and oxidative stress levels, consequently inducing epigenetic reprogramming, and deregulation of several key pathways contributing to therapy resistance and disease progression.
date: 2025
id_scheme: DOI
id_number: 10.11588/heidok.00035898
ppn_swb: 1914897226
own_urn: urn:nbn:de:bsz:16-heidok-358988
date_accepted: 2024-12-18
advisor: HASH(0x55e83af52df8)
language: eng
bibsort: MULLERJANIGLYATL1ANO
full_text_status: public
citation:   Müller, Janina  (2025) GLYATL1, a Novel Player in Endocrine Therapy Resistance in Breast Cancer.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/35898/1/Dissertation_Janina_Mueller.pdf