Biology subjects

Burmester, S.

Publications and source records attributed to Burmester, S..

3 recordsLinked to original sources

bioRxiv2025

GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer

Estrogen receptor alpha (ER)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success. We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses these effects and reduces proliferation under estrogen-deprived conditions. Notably, GLYATL1 expression is positively regulated by estrogen receptor alpha signaling independently of estrogen. These findings reveal GLYATL1 as a metabolic and epigenetic mediator of endocrine therapy resistance, suggesting it as a potential target to overcome AI resistance in luminal breast cancer.

cancer biology↗

bioRxiv2025

PAK1 activation drives divergent resistance mechanisms to aromatase inhibition and Tamoxifen in a luminal A breast cancer model

Breast cancer is the most frequent malignancy and the second leading cause of cancer-related mortality in women worldwide, and is a heterogeneous disease regarding driver mechanisms, therapies, and outcome. Estrogen receptor-positive (ER+) tumors are treated with endocrine therapies such as Tamoxifen or aromatase inhibitors (AI), aimed at disrupting tumor-promoting estrogen signaling. While these therapies are initially effective, resident tumor cells can develop resistance, leading to relapse. The p21-activated kinase 1 (PAK1) is a key regulator of multiple oncogenic signaling pathways and has been implicated in resistance to Tamoxifen. However, it remains unclear, whether PAK1 also affects the response to other endocrine therapies. Using global phosphoproteomic profiling of endocrine resistant cell line models, we observed elevated PAK1 activity in cells resistant to Tamoxifen and to estrogen deprivation, respectively, with further increases following EGF stimulation. Pharmacological inhibition of PAK1 effectively reduced cell proliferation in both resistance models, however, with distinct effects on PAK1 downstream substrates and pathways. In the Tamoxifen resistance context, PAK1 reduces apoptosis via inhibition of the pro-apoptotic protein BAD, whereas in the AI resistance model PAK1 rather triggers proliferation via RAF1. Our findings position PAK1 as a common mediator of resistance to different endocrine therapies and offer insights into the distinct signaling networks that are involved. In summary, our results suggest that targeting PAK1 may present a novel therapeutic strategy to overcome endocrine therapy resistance in ER+ breast cancer, potentially enhancing the efficacy of both Tamoxifen and AI treatments.

cancer biology↗

bioRxiv2020

Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts

HER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes activation of AKT and ERK1/2, contributing to tumour progression and therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, and although they have shown favorable tolerability, their activity as a single agent has proven to be limited. Here we show that phosphorylation and activation of HER3 in luminal breast cancer cells occurs in a paracrine manner and is mediated by NRG1 expressed by cancer-associated fibroblasts (CAFs). Moreover, we uncover an autocrine role of NRG1 in CAFs. This occurs independently of HER3 and results in the induction of a strong migratory and pro-fibrotic phenotype, describing a subset of CAFs with elevated expression of NRG1 and an associated transcriptomic profile that determines their functional properties. Finally, we identified Hyaluronan Synthase 2 (HAS2), a targetable molecule strongly correlated with NRG1, as an attractive player supporting NRG1 - autocrine signaling in CAFs.

cancer biology↗