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Peer-reviewedCC BY 4.0Molecular Oncology

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

  • Luisa Schwarzmüller1,2
  • Janina Müller1,2
  • Efstathios‐Iason Vlachavas1
  • Lukas Beumers1,2
  • Lena Fleischhacker1
  • Sara Burmester1
  • Angelika Wörner1
  • Sabine Karolus1
  • Dominic Helm3
  • Cindy Körner1
  • Stefan Wiemann1
  1. 1Division of Molecular Genome Analysis German Cancer Research Center (DKFZ) Heidelberg Germany
  2. 2Faculty of Biosciences University of Heidelberg Heidelberg Germany
  3. 3Proteomics Core Facility German Cancer Research Center (DKFZ) Heidelberg Germany
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Abstract

Breast cancer is the most frequent malignancy and the second leading cause of cancer‐related mortality in women. Estrogen receptor‐positive (ER+) tumors are treated with endocrine therapies such as tamoxifen or aromatase inhibitors (AI), aimed at disrupting estrogen signaling. While these therapies are initially effective, resident tumor cells can develop resistance, leading to relapse. The p21‐activated kinase 1 (PAK1), a regulator of oncogenic signaling pathways, has been implicated in tamoxifen resistance. However, it remains unclear whether PAK1 also affects the response to other endocrine therapies. Here we show PAK1 activity was elevated in tamoxifen‐resistant and long‐term estrogen‐deprived MCF7 cell lines and showed enhanced responsiveness to EGF stimulation. Inhibition of PAK1 effectively reduced cell proliferation in both models, with distinct effects on PAK1 downstream substrates. In the tamoxifen resistance context, PAK1 inhibition induced activation of the pro‐apoptotic protein BAD and triggered apoptosis while proliferation‐related kinases were suppressed in the estrogen‐deprived model. Our findings position PAK1 as a mediator of resistance to endocrine therapies suggesting that targeting PAK1 may present a novel strategy to overcome endocrine therapy resistance in ER+ breast cancer.

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Cite

BibTeXRIS
BibTeX
@article{schwarzmuller2026pak1,
  title = {{PAK1 activation drives divergent resistance mechanisms to aromatase inhibition and tamoxifen in a luminal: A breast cancer model}},
  author = {Luisa Schwarzmüller and Janina Müller and Efstathios‐Iason Vlachavas and Lukas Beumers and Lena Fleischhacker and Sara Burmester and Angelika Wörner and Sabine Karolus and Dominic Helm and Cindy Körner and Stefan Wiemann},
  journal = {Molecular Oncology},
  year = {2026},
  month = jun,
  doi = {10.1002/1878-0261.70286},
  url = {https://doi.org/10.1002/1878-0261.70286},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - PAK1 activation drives divergent resistance mechanisms to aromatase inhibition and tamoxifen in a luminal: A breast cancer model
AU  - Luisa Schwarzmüller
AU  - Janina Müller
AU  - Efstathios‐Iason Vlachavas
AU  - Lukas Beumers
AU  - Lena Fleischhacker
AU  - Sara Burmester
AU  - Angelika Wörner
AU  - Sabine Karolus
AU  - Dominic Helm
AU  - Cindy Körner
AU  - Stefan Wiemann
PY  - 2026
DA  - 2026/06/05
JO  - Molecular Oncology
DO  - 10.1002/1878-0261.70286
UR  - https://doi.org/10.1002/1878-0261.70286
AB  - Breast cancer is the most frequent malignancy and the second leading cause of cancer‐related mortality in women. Estrogen receptor‐positive (ER+) tumors are treated with endocrine therapies such as tamoxifen or aromatase inhibitors (AI), aimed at disrupting estrogen signaling. While these therapies are initially effective, resident tumor cells can develop resistance, leading to relapse. The p21‐activated kinase 1 (PAK1), a regulator of oncogenic signaling pathways, has been implicated in tamoxifen resistance. However, it remains unclear whether PAK1 also affects the response to other endocrine therapies. Here we show PAK1 activity was elevated in tamoxifen‐resistant and long‐term estrogen‐deprived MCF7 cell lines and showed enhanced responsiveness to EGF stimulation. Inhibition of PAK1 effectively reduced cell proliferation in both models, with distinct effects on PAK1 downstream substrates. In the tamoxifen resistance context, PAK1 inhibition induced activation of the pro‐apoptotic protein BAD and triggered apoptosis while proliferation‐related kinases were suppressed in the estrogen‐deprived model. Our findings position PAK1 as a mediator of resistance to endocrine therapies suggesting that targeting PAK1 may present a novel strategy to overcome endocrine therapy resistance in ER+ breast cancer.
SN  - 1574-7891
SN  - 1878-0261
ER  -