Expression profile of tumour suppressor protein p53 and its regulator MDM2 in a cohort of breast cancer patients in a Tertiary Hospital in Ghana

Background Inactivation or mutation of the tumour suppressor gene p53 or its regulator mouse double minute 2 (MDM2) is the commonest event in breast cancer. These altered genes usually express abnormally high levels of their proteins in many carcinomas. The phenotypic expression of p53 and MDM2 in breast cancer cases in our setting is not known. This study investigated the expression of the tumour suppressor protein p53 and its regulator MDM2, using immunohistochemistry in a Ghana breast cancer cohort. Method A 9-year retrospective cross-sectional study on archived tissue blocks–formalin fixed paraffin embedded tissue (FFPE) was carried out. Demographic data were abstracted. Based on complete clinical data and availability of FFPE archived blocks 203 cases were selected for tissue micro array (TMA) construction. The TMA sections were subjected to immunohistochemistry (IHC) (ER, PR, HER2, p53, and MDM2). Expression of p53 and MDM2 were related to grade and molecular subtypes. Results The age ranged from 17 to 92 years (mean = 49.34 ± 13.74). Most of the cases were high grade; grade II (34.9%) and grade III (55.7%). Fifty-four percent of the cases were triple negative. Invasive ductal carcinoma no special type was the commonest histotype (87.1%). Thirty-six percent (36%) of the cases expressed p53. Significant associations were found between p53 overexpression and histological grade (p = 0.034), triple negative (p = 0.0333) and luminal B (p<0.01) tumors. Most cases (93.1%) were negative for MDM2 expression. Significant association was found between MDM2 and HER2 over-expression as well as Ki-67. There was no significant positive correlation between MDM2 and p53 co-expression (p>0.05). Conclusion The elevated level of p53 expression in the aggressive breast cancer phenotypes (high histological grade and triple negative) in our cohort suggest that P53 elevation may be a poor prognostic marker in our setting. High expression of MDM2 in our cohort with high Ki67; also in cases with Her2/neu overexpression known with predictable poor prognosis in the absence of target therapy suggest MDM2 may be associated with aggressive biological behaviour in our breast cancer cases. The non-significant association of p53 and MDM2 expression in the same cases as also documented by previous studies suggest independent genetic pathway in tumourigenesis.

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p53 Missense Mutation is Associated with Immune Cell PD-L1 Expression in Triple-negative Breast Cancer

10.21203/rs.3.rs-1070659/v1 ◽

2021 ◽

Author(s):

Bin Wang ◽

Kun Wang ◽

Jian Yu ◽

Long Liu ◽

Ke Liang ◽

...

Keyword(s):

Breast Cancer ◽

Missense Mutation ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Immune Cell ◽

Histological Grade ◽

P53 Mutation ◽

Missense Mutations ◽

P53 Expression ◽

Programmed Death

Abstract BackgroundImmunotherapy is an important treatment for triple-negative breast cancer (TNBC). The programmed death ligand 1 (PD-L1) is a pivotal biomarker in TNBC, and its expression is closely related to immunotherapy response. Therefore, the association of p53 expression and mutation and PD-L1 expression was explored. Methods and Results PD-L1 expression and p53 mutation and expression were evaluated by immunohistochemistry. PD-L1 expression and expression levels between p53 mutation (missense and nonsense) and wild type; no-expression/loss vs. expression; and missense vs. nonsense groups were compared. PD-L1 expression was found mainly in tumor-infiltrating immune cells (ICs) in TNBC. Positive PD-L1 expression was associated with a high Ki67 index. There was a significant association between p53 mutation, especially missense mutation and higher histological grade, and PD-L1 expression in ICs. Compared with p53 nonsense mutation, cases with missense mutations tended to display more PD-L1 positive ICs. However, PD-L1 expression in ICs was not significantly different between the p53 mutation and expression groups. Conclusionsp53 missense mutation is partially involved in the regulatory expression of PD-L1. Both p53 missense mutation and PD-L1 expression may be potential targets for improving immunotherapy response in TNBC.

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Value of Systemic Staging in Asymptomatic Early Breast Cancer

Revista Brasileira de Ginecologia e Obstetrícia / RBGO Gynecology and Obstetrics ◽

10.1055/s-0038-1666997 ◽

2018 ◽

Vol 40 (07) ◽

pp. 403-409 ◽

Cited By ~ 1

Author(s):

Gregório Soares ◽

Allan Pereira ◽

Mariana Vilas Boas ◽

Victor Vaisberg ◽

Maria Magalhães ◽

...

Keyword(s):

Breast Cancer ◽

Early Breast Cancer ◽

Triple Negative ◽

Ductal Carcinoma ◽

Histological Grade ◽

Growth Factor Receptor ◽

Distant Metastases ◽

Routine Practice ◽

Her2 Positive ◽

Asymptomatic Patients

Objective Metastases are rare in early breast cancer (EBC), and international guidelines recommend against routine systemic staging for asymptomatic patients. However, imaging exams remain widely employed in the clinical practice. The aim of the present study is to evaluate the value of imaging for systemic staging in EBC. Methods A retrospective analysis of newly-diagnosed breast cancer (BC) patients was performed. Clinical data including BC subtype, stage, presence of symptoms at diagnosis and instrumental procedures performed for staging were recorded. Results A total of 753 patients were included, with a median age of 57 years. The majority of the patients underwent at least 1 imaging procedure (91%); had invasive ductal carcinoma (83.5%); histological grade 2 (51.4%); stage II (61.8%); and luminal subtype (67.9%). Among the 685 (91%) patients who underwent any radiologic staging, distant metastases (DMs) were detected in 32 (4.7%). In the univariate analyses, stage IIb and pathological lymph node involvement (pN1) showed a statistically significant association with the presence of DMs, versus only a trend for triple negative and human epidermal growth factor receptor 2 (Her2) positive subtype. In an exploratory analysis performed in this same subgroup, when unfavorable biology (triple negative or Her2 positive) was present, patients had a DM rate of 14.4%, one of the highest reported at this stage of the disease. Conclusion Early breast cancer has a low prevalence of DM at the initial evaluation, and systemic staging of asymptomatic, unselected patients is not warranted as a routine practice. However, we have identified subgroups of patients to whom a full staging could be indicated.

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Apoptosis regulator Bcl-2 is an independent prognostic marker for worse overall survival in triple-negative breast cancer patients

The International Journal of Biological Markers ◽

10.5301/ijbm.5000291 ◽

2017 ◽

Vol 33 (1) ◽

pp. 109-115 ◽

Cited By ~ 10

Author(s):

Petar Ozretic ◽

Ilija Alvir ◽

Bozena Sarcevic ◽

Zeljko Vujaskovic ◽

Zrinka Rendic-Miocevic ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Histological Grade ◽

Prognostic Significance ◽

Clinical Variable ◽

Breast Cancer Patients ◽

Roc Curve Analysis ◽

P53 Expression

Background: The objective of this study was to examine the prognostic significance of carbonic anhydrase IX (CAIX), an endogenous marker for tumor hypoxia; the cellular tumor antigen p53; and the apoptosis regulator Bcl-2, in triple-negative breast cancer (TNBC) patients. Methods: Immunohistochemically determined expression of CAIX, p53, Bcl-2 and proliferation factor Ki-67, analyzed in 64 paraffin-embedded TNBC tissue samples, was used to assess their relation to clinicopathological variables and prognostic implications for overall survival (OS). Results: Bcl-2 expression was negatively correlated with histological grade of tumor, while expression of p53 was positively correlated with the same clinical variable (p = 0.036 and p = 0.033, respectively). The p53 expression was also positively correlated with tumor size (p = 0.010). Survival analysis showed that patients with high Bcl-2 expression (above cutoff value determined by receiver operator characteristic [ROC] curve analysis) had shorter OS (p = 0.020). The same was observed for patients with tumors larger than 5 cm (p = 0.034) or positive lymph nodes (p = 0.004). Among all 3 examined markers, multivariate analysis showed that only Bcl-2 expression was a strong independent prognostic indicator for decreased OS (hazard ratio [HR] = 15.16, 95% confidence interval [95% CI], 2.881-79.727, p = 0.001). Conclusions: Elevated expression of Bcl-2 was an independent prognostic factor for poorer OS in TNBC and as such a significant marker for tumor aggressiveness.

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Correlation of CK5 and EGFR with Clinicopathological Profile of Triple-Negative Breast Cancer

Pathology Research International ◽

10.1155/2014/141864 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Neelam Sood ◽

Jitendra Singh Nigam

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Ductal Carcinoma ◽

Histological Grade ◽

Positive Association ◽

Ki 67 ◽

Significant Positive Association ◽

Egfr Expression ◽

Clinicopathological Profile

Purpose. Triple-negative breast cancer (TNBC) is defined by the loss of expression of ER, PR, and Her2neu expressions. The aim of this study was to examine the expression of the EGFR, CK5, and Ki-67 among triple-negative breast cancer cases and to correlate the expression of the basal markers with the clinicopathological prognostic parameters. Materials and Methods. Thirty-six female patients with TNBC based on ER, PR, and the HER2neu negativities were studied by immunohistochemistry for EGFR, CK5, and Ki-67 expression. Statistical analysis was done using the SPSS software version 20. Results. The mean and median ages were 45.18 years and 46.70 years, respectively. Infiltrating ductal carcinoma NOS was the predominant histopathological type (29/36 [80.6%]). The commonest histological grade was grade 2 (17/36 [47.2%]). Tumour necrosis was seen in 16/36 (44.4%) patients. Infiltrative margins were shown in 69.44% (25/36) cases. Ki-67 was positive in 80.56% (29/36) cases, 61.11% (22/36) were CK5-positive, and 86.11% (31/36) were EGFR-positive. The only significant positive association observed was between the CK5 and histological grade (P<0.05). Conclusion. CK5 shows a statistically significantly correlation with TNBC histological grade. The majority of the specimens show EGFR expression. Therefore TNBCs could potentially benefit from EGFR-targeted therapeutic strategies.

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Targeting claudin-4 enhances chemosensitivity of triple negative breast cancer

10.21203/rs.2.12416/v1 ◽

2019 ◽

Author(s):

Yi Luo ◽

Shingo Kishi ◽

Takamitsu Sasaki ◽

Hitoshi Ohmori ◽

Rina Fujiwara-Tani ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Ductal Carcinoma ◽

Histological Grade ◽

Receptor Subtype ◽

Therapeutic Effects ◽

Model Combination ◽

Metastasis Model ◽

Mcf 7

Abstract Background Triple negative breast cancer (TNBC) possesses highly aggressive phenotype, treatment with limited options, and a poor prognosis. In this study, we examined the therapeutic effect of anti-claudin (CLDN)-4 extracellular domain antibody, 4D3, on TNBC. Methods The expression of CLDN4 and CLDN1 in invasive ductal carcinoma (IDC) was examined in 78 IDCs (from 2004 to 2009 in a single center). CLDN expression and the effect of 4D3 on proliferation were examined in in human IDC cell lines MCF-7 (luminal subtype) and MDA-468 (TNBC). Results In IDC cases, CLDN1 had lower expression than CLDN4 and correlated with histological grade. In contrast, expression of CLDN4 correlated with histological grade, receptor subtype, and stage. CLDN4 expression in the two cells was at the same level. In both cells, paclitaxel (PTX)-induced growth suppression was enhanced by 4D3. Furthermore, 4D3 increased both intracellular PTX concentration (in both cells) and apoptosis. In the mouse model, 4D3 promoted the antitumor effect of PTX on subcutaneous tumors and reduced lung metastasis. The combination of PTX and 4D3 reduced M2 macrophages and mesenchymal stem cells in the tumor. 4D3 also reduced stemness of the tumors in association with increase in the intratumoral pH. Moreover, concurrent treatment of 4D3, PTX, or tamoxifen; or with PTX and tamoxifen in MDA-468 also showed the same level of antitumor activity and survival as MCF-7. Furthermore, in bone metastasis model, combination of PTX and bisphosphonate with 4D3 promoted tumor growth in both cells. Conclusions CLDN4 targeting of the antibody facilitated existing therapeutic effects.

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Low KIBRA Expression Is Associated with Poor Prognosis in Patients with Triple-Negative Breast Cancer

Medicina ◽

10.3390/medicina57080837 ◽

2021 ◽

Vol 57 (8) ◽

pp. 837

Author(s):

So-Woon Kim ◽

Jinah Chu ◽

Sung-Im Do ◽

Kiyong Na

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Histological Grade ◽

Growth Factor Receptor ◽

Hippo Signaling ◽

Luminal A ◽

Luminal B ◽

Epidermal Growth

Background and Objectives: Kidney and brain protein (KIBRA) is a protein encoded by the WW and C2 domain containing 1 (WWC1) gene and is involved in the Hippo signaling pathway. Recent studies have revealed the prognostic value of KIBRA expression; however, its role in breast cancer remains unclear. The aim of this study was to examine KIBRA expression in relation to the clinical and pathological characteristics of patients with breast cancer and to disease outcomes. Materials and Methods: We analyzed the expression of KIBRA and its correlation with event-free survival (EFS) outcomes in resected samples from 486 patients with breast cancer. Results: KIBRA expression was significantly different among the molecular subgroups (low KIBRA expression: luminal A, 46.7% versus 50.0%, p = 0.641; luminal B, 32.7% versus 71.7%, p < 0.001; human epidermal growth factor receptor 2 (HER2)-enriched, 64.9% versus 45.5%. p = 0.001; triple-negative, 73.6% versus 43.8%, p < 0.001). Low KIBRA expression was also associated with high nuclear grade (60.4% versus 37.8%, p < 0.001), high histologic grade (58.7% versus 37.0%, p < 0.001), and estrogen receptor (ER) negativity (54.2% versus 23.6%, p < 0.001). Low KIBRA expression was significantly associated with poor EFS (p = 0.041; hazard ratio (HR) 1.658; 95% confidence interval (CI), 1.015–2.709). Low KIBRA expression was an independent indicator of poor prognosis (p = 0.001; HR = 3.952; 95% CI = 1.542–10.133) in triple-negative breast cancer (TNBC). Conclusion: Low KIBRA expression was associated with higher histological grade, ER negativity and poor EFS of breast cancer. In particular, our data highlight KIBRA expression status as a potential prognostic marker for TNBC.

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ROLE OF TUMOUR SUPPRESSOR GENE P53 IN TRIPLE NEGATIVE BREAST CANCER

International Journal of Anatomy and Research ◽

10.16965/ijar.2017.402 ◽

2017 ◽

Vol 5 (4.2) ◽

pp. 4585-4589

Author(s):

Priya S Patil ◽

◽

Jaydeep N Pol ◽

Ashalata D Patil ◽

◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Tumour Suppressor

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Immunohistochemical analysis of CD155 expression in triple-negative breast cancer patients

PLoS ONE ◽

10.1371/journal.pone.0253176 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0253176

Author(s):

Katsuhiro Yoshikawa ◽

Mitsuaki Ishida ◽

Hirotsugu Yanai ◽

Koji Tsuta ◽

Mitsugu Sekimoto ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Tumor Cells ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Expression Profiles ◽

Histological Grade ◽

Relapse Free Survival ◽

Free Survival ◽

Antitumor Immunotherapy

Introduction CD155 is an immune checkpoint protein. Its overexpression is an indicator of poor prognosis in some types of cancer. However, the significance of CD155 expression in patients with triple-negative breast cancer, and the relationship between CD155 and programmed death-ligand 1 (PD-L1) expression, have not yet been analyzed in detail. Methods Using immunohistochemical staining and tissue microarrays, we analyzed the expression profiles of CD155 and PD-L1 in 61 patients with triple-negative breast cancer. Relapse-free survival and overall survival rates were compared according to CD155 expression. The correlation between CD155 expression and clinicopathological factors, including PD-L1 expression (using SP142 and 73–10 assays), was also examined. Results CD155 expression was noted in 25 patients (41.0%) in this cohort. CD155 expression did not correlate with pathological stage, histological grade, Ki-67 labeling index, or stromal tumor-infiltrating lymphocytes. Only PD-L1 expression in tumor cells by SP142 assay significantly correlated with CD155 expression (p = 0.035); however, PD-L1 expression in tumor cells by 73–10 assay did not show a correlation (p = 0.115). Using the 73–10 assay, 59% of patients showed CD155 and/or PD-L1 expression in tumor cells. Moreover, using the SP142 assay, 63.3% of patients showed CD155 and/or PD-L1 expression in immune cells. CD155 expression did not correlate with either relapse-free survival or overall survival (p = 0.485 and 0.843, respectively). Conclusions CD155 may be a novel target for antitumor immunotherapy. The results of this study indicate that CD155 may expand the pool of candidates with triple-negative breast cancer who could benefit from antitumor immunotherapy.

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