SUMOylation proteins in breast cancer

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.

Clinical and biological significance of RAD51 expression in breast cancer: a key DNA damage response protein

“…To test the specificity of the used antibody and to confirm the expression of RAD51 in specific BC cell lines corresponding to molecular classes of BC, Western blotting and RPPA were performed as previously described [24][25][26]. Four different cell lines were used; luminal phenotype MCF-7 cell lines (characterised by positive expression of ER and BRCA1, ATCC) and MDA-MB-436 (ER-and EGFR+, CLS) which were grown in RPMI1640 (Sigma, UK).…”

Molecular Mechanisms Underlying Lymphovascular Invasion in Invasive Breast Cancer

“…For example, high KU70/KU80 expression correlated with a positive LVI status [90]. Members of the SUMO (small ubiquitin-like modifier protein) family have shown correlations with LVI; positive LVI was associated with loss of nuclear expression but positive cytoplasmic expression of PIAS1 and UBC9, and with the expression of PIAS4 [91]. This exemplifies the importance of the SUMO pathways in LVI.…”

SUMO pathway components as possible cancer biomarkers

“…Colon Diagnosis, prognosis [61] Gastric Diagnosis, prognosis, therapeutic predictivity [62,63] Prostate Diagnosis [64] Breast Prognosis [44] PIAS3 Lung, breast, prostate, colorectal, brain Diagnosis [65,66] Ovarian, endometrial Diagnosis [67] Squamous cell carcinoma of the lung Diagnosis [68] Gastric Diagnosis, prognosis [69] PIAS4 Gastric Therapeutic predictivity [63] Breast Prognosis [70] MDS Diagnosis, progression [71] RanBP2 Multiple myeloma Diagnosis [72] Small cell lung cancer Diagnosis [73] Inflammatory myofibroblastic tumor Diagnosis, prognosis, therapeutic predictivity, risk assessment [74,75] Acute myelomonocytic leukemia Diagnosis, risk assessment [76,77] 8p11 myeloproliferative syndrome Diagnosis, risk assessment [78] Pc2 Hepatocellular carcinoma Prognosis [79] TRIM19 AML Diagnosis [80] TRIM27 Endometrial Prognosis [81] Colon Prognosis [82] Ovarian Prognosis, therapeutic predictivity [83] SENP1 Prostate Diagnosis, prognosis, therapeutic predictivity [84][85][86] Pancreatic ductal adenocarcinoma Diagnosis, prognosis [87] SENP2 Bladder Diagnosis [88] Hepatocellular carcinoma Diagnosis [89] SENP3 Colon, rectum, ovarian, lung, oral squamous cell carcinoma Diagnosis [90,91] …”

“…Remarkably, not only the expression levels but also the Ubc9 intracellular localization can be used to evaluate breast cancer aggressiveness. Indeed, tumors with positive nuclear and negative cytoplasmic Ubc9 staining in immunohistochemistry (IHC) showed good prognostic features as compared with cytoplasmic positiveUbc9 breast cancer [44]. Genetic variability may also affect Ubc9 expression and activity and may have an impact on breast cancer occurrence and progression.…”