SUMOylation proteins in breast cancer
Alaa T Alshareeda1, Ola H Negm, Andrew R Green
1Department of Histopathology and School of Molecular Medical Sciences, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK, mrxaa31@nottingham.ac.uk.
Abstract:
Small Ubiquitin-like Modifier proteins (or SUMO) modify the function of protein substrates involved in various cellular processes including DNA damage response (DDR). It is becoming apparent that dysregulated SUMO contribute to carcinogenesis by affecting post-transcriptional modification of key proteins. It is hypothesised that SUMO contributes to the aggressive nature of breast cancer particularly those associated with features similar to breast carcinoma arising in patients with BRCA1 germline mutations. This study aims to assess the clinical and biological significance of three members of SUMO in a well-characterised annotated series of BC with emphasis on DDR. The study cohort comprised primary operable invasive BC including tumours from patients with known BRCA1 germline mutations. SUMO proteins PIAS1, PIAS4 and UBC9 were assessed using immunohistochemistry utilising tissue microarray technology. Additionally, their expression was assessed using reverse phase protein microarray utilising different cell lines. PIAS1 and UBC9 showed cytoplasmic and/or nuclear expression while PIAS4 was detected only in the nuclei. There was a correlation between subcellular localisation and expression of the nuclear transport protein KPNA2. Tumours showing positive nuclear/negative cytoplasmic expression of SUMO featured good prognostic characteristics including lower histologic grade and had a good outcome. Strong correlation with DDR-related proteins including BRCA1, Rad51, ATM, CHK1, DNA-PK and KU70/KU80 was observed. Correlation with ER and BRCA1 was confirmed using RPPA on cell lines. SUMO proteins seem to play important role in BC. Not only expression but also subcellular location is associated with BC phenotype.
Insights
Small Ubiquitin-like Modifier (SUMO) proteins influence DNA damage response and are implicated in breast cancer (BC) aggressiveness. Their nuclear localization correlates with better BC prognosis and links to DNA repair proteins.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Small Ubiquitin-like Modifier (SUMO) proteins regulate key cellular processes, including DNA damage response (DDR).
- Dysregulated SUMOylation is linked to carcinogenesis through altered post-transcriptional modification of proteins.
- SUMO's role in aggressive breast cancer (BC), particularly BRCA1-mutated types, warrants investigation.
Purpose of the Study:
- To evaluate the clinical and biological significance of PIAS1, PIAS4, and UBC9 (SUMO proteins) in breast cancer.
- To investigate the association between SUMO protein expression, subcellular localization, and DNA damage response (DDR) pathways.
- To explore the correlation of SUMO proteins with established breast cancer prognostic markers and BRCA1 status.
Main Methods:
- Immunohistochemistry on tissue microarrays of primary invasive breast cancer (BC) specimens.
- Reverse phase protein microarray (RPPA) analysis of SUMO protein expression in cell lines.
- Assessment of PIAS1, PIAS4, and UBC9 expression and subcellular localization (nuclear vs. cytoplasmic).
Main Results:
- PIAS1 and UBC9 exhibited cytoplasmic and/or nuclear localization, while PIAS4 was exclusively nuclear.
- Positive nuclear/negative cytoplasmic SUMO expression correlated with favorable prognostic features (e.g., lower histologic grade) and better patient outcomes.
- Significant correlations were observed between SUMO protein expression and DDR-related proteins (BRCA1, Rad51, ATM, CHK1, DNA-PK, KU70/KU80).
Conclusions:
- SUMO proteins play a significant role in breast cancer biology.
- Both the expression level and subcellular localization of SUMO proteins are associated with breast cancer phenotype and prognosis.
- SUMOylation pathways may represent potential therapeutic targets in breast cancer, especially in BRCA1-deficient tumors.
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