Proteomic profiling reveals that ESR1 mutations enhance cyclin-dependent kinase signaling
(2024) In Scientific Reports 14. p.1-16- Abstract
Three quarters of all breast cancers express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancer, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and without direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry based proteomic approach to profile the protein and... (More)
Three quarters of all breast cancers express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancer, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and without direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and mTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells. Our study is the first proteome-centric characterization of ESR1 mutant models, out of which we confirm estrogen independence of ER mutants and reveal the enrichment of immune signaling pathways at the proteomic level.
(Less)
- author
- organization
-
- LUCC: Lund University Cancer Centre
- Breast cancer Proteogenomics (research group)
- BioMS (research group)
- Translational Oncogenomics (research group)
- LTH Profile Area: Engineering Health
- epIgG (research group)
- SEBRA Sepsis and Bacterial Resistance Alliance (research group)
- Infection Medicine Proteomics (research group)
- publishing date
- 2024-03-22
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Humans, Female, Cyclin-Dependent Kinases/genetics, Proteome/genetics, Proteomics, Estrogen Receptor alpha/genetics, Breast Neoplasms/pathology, Mutation, Estrogens, Receptors, Estrogen/genetics, Phosphoproteins/genetics
- in
- Scientific Reports
- volume
- 14
- article number
- 6873
- pages
- 1 - 16
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85188337360
- pmid:38519482
- ISSN
- 2045-2322
- DOI
- 10.1038/s41598-024-56412-8
- project
- Proteogenomic analysis of ESR1 mutated cancers
- language
- English
- LU publication?
- yes
- id
- 161979b2-f6d8-4bfd-8810-34380c865810
- date added to LUP
- 2024-03-28 06:56:01
- date last changed
- 2024-04-16 14:25:29
@article{161979b2-f6d8-4bfd-8810-34380c865810, abstract = {{<p>Three quarters of all breast cancers express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancer, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and without direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and mTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells. Our study is the first proteome-centric characterization of ESR1 mutant models, out of which we confirm estrogen independence of ER mutants and reveal the enrichment of immune signaling pathways at the proteomic level.</p>}}, author = {{De Marchi, Tommaso and Lai, Chun-Fui and Simmons, Georgia M and Goldsbrough, Isabella and Harrod, Alison and Lam, Thai and Buluwela, Lakjaya and Kjellström, Sven and Brueffer, Christian and Saal, Lao H and Malmström, Johan and Ali, Simak and Niméus, Emma}}, issn = {{2045-2322}}, keywords = {{Humans; Female; Cyclin-Dependent Kinases/genetics; Proteome/genetics; Proteomics; Estrogen Receptor alpha/genetics; Breast Neoplasms/pathology; Mutation; Estrogens; Receptors, Estrogen/genetics; Phosphoproteins/genetics}}, language = {{eng}}, month = {{03}}, pages = {{1--16}}, publisher = {{Nature Publishing Group}}, series = {{Scientific Reports}}, title = {{Proteomic profiling reveals that ESR1 mutations enhance cyclin-dependent kinase signaling}}, url = {{http://dx.doi.org/10.1038/s41598-024-56412-8}}, doi = {{10.1038/s41598-024-56412-8}}, volume = {{14}}, year = {{2024}}, }