Immunohistochemical evaluation of Cyclin D1 and β-Catenin expression in subtypes of triple-negative breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12553-e12553
Author(s):  
Tatiana N. Gudtskova ◽  
Larisa N. Vashchenko ◽  
Nikolay S. Karnaukhov ◽  
Mramza V. Kvarchiya ◽  
Ekaterina S. Bosenko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Field Of View ◽  
Membrane Expression ◽  
Cytoplasmic Staining ◽  
The Difference ◽  
Student’S T ◽  
High Cyclin

e12553 Background: The purpose of the study was to reveal characteristics of Cyclin D1 and β-Catenin expression in subtypes of triple negative breast cancer (TNBC). Methods: The study included 60 patients diagnosed with verified TNBC (T1N1M0/T2N0M0, ER-/PR-/Her2-). Immunohistochemical staining with CK5/6, EGFR, Cyclin D1, β-Catenin antibodies was performed. Basal-like (BL) subtype was identified when > 25% cells were CK5/6+ and/or EGFR+ (any staining). The expression of β-Catenin was assessed by its location: the membrane, cytoplasm, nucleus. Cells with negative staining on the membrane and cytoplasmic staining were counted and calculated as a percentage of the total number of tumor cells. Nuclear expression of β-Catenin was considered positive with at least 1 positively stained cell in the field of view at x200 magnification. Parametric statistical methods were used. Significance of the difference between the two means was assessed by the Student's t-test. Results: A number of TNBC samples showed Cyclin D1 overexpression. The loss of β-Catenin on the cell membrane and its abnormal accumulation in the cytoplasm was significantly more frequent in TNBC with Cyclin D1 overexpression. These processes were more pronounced in BL cancers. Loss of membrane expression in BL cancers: 29.6±6.1 and 58±7.4%; accumulation in the cytoplasm: 33.4±5.4 and 63.3±7.2%, with low and high Cyclin D1 respectively. Loss of membrane expression in non-BL cancers: 17.6±3.8 and 33.3±4.3%; accumulation in the cytoplasm: 27.3±6.3 and 49.5±8.2%, with low and high Cyclin D1 respectively. Only BL TNBC demonstrated β-catenin translocation to the nucleus (up to 20 stained cells in the field of view): in 33.3% tumors with Cyclin D1 overexpression and in 12% of tumors with its low expression. Conclusions: Levels of expression of β-catenin and Cyclin D1 in TNBC may have predictive value, and the choice of these biomarkers as targets will improve the treatment with new-generation medications.

Ki-67 and Cyclin D1 in subtypes of triple-negative breast cancer with different androgen profiles.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12552-e12552 ◽  
Author(s):  
Larisa N. Vashchenko ◽  
Nikolay S. Karnaukhov ◽  
Tatiana N. Gudtskova ◽  
Mramza V. Kvarchiya ◽  
Elena A. Karnaukhova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Test Results ◽  
Ki 67 ◽  
Cyclin Dependent Kinases ◽  
The Difference ◽  
Student’S T ◽  
High Cyclin

e12552 Background: The purpose of the study was to analyze Ki-67 and Cyclin D1 expression in subtypes of triple negative breast cancer (TNBC) with different androgen profiles. Methods: Tissues of 60 patients with verified TNBC (T1N1M0/T2N0M0, ER-/PR-/Her2-) were studied. Immunohistochemical staining was performed with antibodies to androgen receptors (AR), CK5/6, Ki-67, Cyclin D1, and EGFR. Basal-like (BL) subtype was identified when > 25% cells were CK5/6+ and/or EGFR+ (any staining). Tumors with ≥10% positively stained cells were considered AR+. Parametric statistical methods were used. Significance of the difference between the two means was assessed by the Student's t-test. Results: BL TNBC showed significantly higher Ki-67 expression (81.9±3.1%), compared to other subtypes (70.8±3.1%), p < 0.05. A number of TNBC samples demonstrated Cyclin D1 overexpression ( > 30% stained cells) with no correlation with Ki-67 expression (r = 0.12). High Cyclin D1 levels were less common in BL TNBC (32.4% tumors), compared to other subtypes (43.5% tumors), but its average values were significantly higher (89.9±4.7% vs. 66.5±6.6%, p < 0.05). AR+ tumors were observed in 11 cases (18.3%). Levels of Ki-67 were similar in TNBC with different AR profiles. The percentage of BL tumors was similar in AR+ and AR- cancers (63.6% and 61.3%, respectively). Expression of Cyclin D1 was more frequent in AR+ TNBC (45.5%), vs. 34.7% in АR-. Average levels of Cyclin D1 were significantly higher in AR+ tumors (51.8±13.7%), vs. AR- (31.6±5.1%). Conclusions: TNBC differs in the Cyclin D1 leves; some tumors show its overexpression. Inhibition of cyclin-dependent kinases blocks the cell cycle, which may be useful in the TNBC treatment, which currently has no targets for therapy.

scholarly journals TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3557
Author(s):  
Charu Kothari ◽  
Alisson Clemenceau ◽  
Geneviève Ouellette ◽  
Kaoutar Ennour-Idrissi ◽  
Annick Michaud ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Effective Treatment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Study Analysis ◽  
Tumor Aggressiveness ◽  
Domain Family ◽  
Proliferative Index ◽  
Tumorigenic Potential ◽  
The Difference

Triple-negative breast cancer (TNBC) is a major concern among the different subtypes of breast cancer (BC) due to the lack of effective treatment. In a previous study by our group aimed at understanding the difference between TNBC and non-TNBC tumors, we identified the gene TBC1 domain family member 9 (TBC1D9), the expression of which was lower in TNBC as compared to non-TNBC tumors. In the present study, analysis of TBC1D9 expression in TNBC (n = 58) and non-TNBC (n = 25) patient tumor samples validated that TBC1D9 expression can differentiate TNBC (low) from non-TNBC (high) samples and that expression of TBC1D9 was inversely correlated with grade and proliferative index. Moreover, we found that downregulation of the TBC1D9 gene decreases the proliferation marginally in non-TNBC and was associated with increased migratory and tumorigenic potential in both TNBC and luminal BC cell lines. This increase was mediated by the upregulation of ARL8A, ARL8B, PLK1, HIF1α, STAT3, and SPP1 expression in TBC1D9 knockdown cells. Our results suggest that TBC1D9 expression might limit tumor aggressiveness and that it has a differential expression in TNBC vs. non-TNBC tumors.

scholarly journals Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

2016 ◽  
Vol 38 (3) ◽  
pp. 1003-1014 ◽  
Author(s):  
Aiyu Zhu ◽  
Yan Li ◽  
Wei Song ◽  
Yumei Xu ◽  
Fang Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

scholarly journals Gomisin G Inhibits the Growth of Triple-Negative Breast Cancer Cells by Suppressing AKT Phosphorylation and Decreasing Cyclin D1

2018 ◽  
Vol 26 (3) ◽  
pp. 322-327 ◽  
Author(s):  
Sony Maharjan ◽  
Byoung Kwon Park ◽  
Su In Lee ◽  
Yoonho Lim ◽  
Keunwook Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Akt Phosphorylation

scholarly journals Immunohistochemical evaluation of Ki-67, Cyclin D1 and β-catenin expression in the subtypes of triple negative breast cancer

2019 ◽  
Vol 100 (2) ◽  
pp. 239-244
Author(s):  
L N Vashchenko ◽  
T N Gudtskova ◽  
E M Nepomnyashchaya ◽  
N S Karnaukhov ◽  
M V Kvarchiya
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Clinical Stage ◽  
Progesterone Receptors ◽  
Ki 67 ◽  
Average Value ◽  
Abnormal Accumulation ◽  
High Level

Aim. To evaluate the expression levels of Ki-67 and cyclin D1 and β-catenin in the subtypes of triple negative breast cancer. Methods. The study was conducted on the surgical material from 60 patients of clinical stage 2A (T1N1M0 or T2N0M0) who were treated at the Rostov Research Institute of Oncology from 2012 to 2015. For immunohistochemistry, antibodies to estrogen and progesterone receptors, cytokeratins 5/6, Ki-67, cyclin D1, β-catenin, HER2/neu and EGFR proteins were used. Results. Triple negative breast cancer with the signs of basal epithelium was found to have a significantly higher expression level of Ki-67 compared to non-basal-like one. In some part of triple negative breast cancer samples overexpression of cyclin D1 was observed. The high level of cyclin D1 in the basal-like subtype was less common than in the subtypes without the signs of basal epithelium, but its average value was significantly higher. In triple negative cancer with cyclin D1 overexpression, the loss of β-catenin on the cell membrane and its abnormal accumulation in the cytoplasm was significantly more frequent. β-catenin translocation into the cell nucleus was observed only in basal-like triple negative cancer, and 2 times more often in case of cyclin D1 overexpression. Conclusion. In triple negative breast cancer tumors with overexpression of cyclin D1 and abnormal expression of β-catenin are observed in some cases; these biomarkers can be considered as potential therapeutic targets for this group of tumors.

scholarly journals A novel sequential treatment of palbociclib enhances the effect of cisplatin in RB-proficient triple-negative breast cancer

2020 ◽  
Author(s):  
Yajing Huang ◽  
Hao Wu ◽  
Xingrui Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Sequential Treatment ◽  
Phase Cell ◽  
Dependent Manner ◽  
Effect Of Pd

Abstract Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy lack of sensitivity to chemo-, endocrine and targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been proven to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. So we investigated that whether CDK4/6 inhibitor palbociclib (PD) could enhance effects of cisplatin (CDDP) on TNBC.Methods: The effects of different drug regimens of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells were assessed in vitro and vivo. MDA-MB-468 and RB-overexpression MDA-MB-468 cells were used to assess the effect of PD-CDDP regimen in vitro. Immunoblotting illustrated cyclin D1/RB/E2F axis signaling pathway.Results: PD induced G1 phase cell cycle arrest in MDA-MB-231 cell line. However, synchronous treatment with PD and CDDP for 24h, PD used for 24h and then followed by CDDP or CDDP used for 24h and then followed by PD all had no influence on cell apoptosis of MDA-MB-231 cells. We further investigated the effect of PD or CDDP withdrawal on sequential treatment and found that PD used for 48h and then withdrawn for 48h followed by CDDP (PD-CDDP) could significantly increase apoptosis, inhibit cell viability and colony formation of MDA-MB-231 cells, while in other regimens PD and CDDP represented additive or antagonistic response. Preferential use of PD could increase DNA damage by CDDP as measured through γH2AX. These findings above were negative in sh-MDA-MB-231 cells and cell function experiments of MDA-MB-468 and RB-overexpression MDA-MB-468 cells could draw similar conclusions, which indicated that PD enhanced the sensitivity of TNBC cells to CDDP in a RB dependent manner. In vivo, this combination treatment inhibited tumor growth and Ki-67 expression compared with single drug treatments in MDA-MB-231 xenograft models. Western blotting analysis presented that PD enhanced sensitivity to CDDP through CDK4/6-cyclin D-RB-E2F pathway. Conclusions: Pre-treatment with PD synchronized tumor cell cycle through CDK4/6-cyclin D1-RB-E2F pathway, which could increase anti-tumor effect of CDDP. PD-CDDP might be an effective treatment for RB-proficient TNBC patients.

scholarly journals High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer

2019 ◽  
Vol 21 (1) ◽  
pp. 217 ◽  
Author(s):  
Eriko Katsuta ◽  
Li Yan ◽  
Takashi Takeshita ◽  
Kerry-Ann McDonald ◽  
Subhamoy Dasgupta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Triple Negative Breast Cancer ◽  
Target Genes ◽  
Triple Negative ◽  
Dna Amplification ◽  
High Expression ◽  
Inclusion Criteria ◽  
Gene Sets ◽  
The Difference

DNA abnormalities are used in inclusion criteria of clinical trials for treatments with specific targeted molecules. MYC is one of the most powerful oncogenes and is known to be associated with triple-negative breast cancer (TNBC). Its DNA amplification is often part of the targeted DNA-sequencing panels under the assumption of reflecting upregulated signaling. However, it remains unclear if MYC DNA amplification is a surrogate of its upregulated signaling. Thus, we investigated the difference between MYC DNA amplification and mRNA high expression in TNBCs utilizing publicly available cohorts. MYC DNA amplified tumors were found to have various mRNA expression levels, suggesting that MYC DNA amplification does not always result in elevated MYC mRNA expression. Compared to other subtypes, both MYC DNA amplification and mRNA high expression were more frequent in the TNBCs. MYC mRNA high expression, but not DNA amplification, was significantly associated with worse overall survival in the TNBCs. The TNBCs with MYC mRNA high expression enriched MYC target genes, cell cycle related genes, and WNT/β-catenin gene sets, whereas none of them were enriched in MYC DNA amplified TNBCs. In conclusion, MYC mRNA high expression, but not DNA amplification, reflects not only its upregulated signaling pathway, but also clinical significance in TNBCs.

scholarly journals Dasatinib/Celecoxib combination: A new hope in triple negative breast cancer treatment

2021 ◽  
Author(s):  
Nermine Aly Moussa ◽  
Mahira Mohamed ◽  
Medhat Haroun ◽  
Maged Helmy Wasfy
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Caspase 3 ◽  
Triple Negative ◽  
Signaling Cascades ◽  
Migration And Invasion ◽  
Protein Levels ◽  
Cox 2 ◽  
Active Caspase

Abstract Despite the tremendous efforts to implement new paradigms for breast cancer, the disease still remains a major challenge worldwide. Genetic deregulation is evident in all breast cancer subtypes and comprises a multitude of mutated genes and deregulated signaling cascades. In this sense, co-targeting Src and COX-2 signaling cascades have attracted fervent interest. This work explored the probable anti-carcinogenic effects of Dasatinib as a Src inhibitor, Celecoxib as a selective COX-2 inhibitor, and their combination in MDA-MB-231 triple-negative breast cancer cell line. Drug growth inhibition 50 (GI50) was determined using the MTT assay and the obtained results were analyzed using CompuSyn 3.0.1 software. MDA-MB-231 cells were divided into four treatment groups including a positive control, Dasatinib-treated, Celecoxib-treated, and combination-treated groups. Standard sandwich ELISA was used for the determination of the protein levels of c-Src, Bcl-2, p-AKT, FAK, PGE2, VEGF, and cyclin D1. Active caspase-3 was determined colorimetrically and the expression of COX-2 and c-Src genes was quantitatively determined via quantitative real-time polymerase chain reaction. The GI50 for Dasatinib was 0.05699 µM while that for Celecoxib was 69.0976 µM. Dasatinib up-regulated c-Src gene while Celecoxib and Dasatinib/Celecoxib combination down-regulated such expression level. COX-2 gene was down-regulated by Celecoxib while it was up-regulated by both Dasatinib and Dasatinib/Celecoxib combination. On one hand, Dasatinib, Celecoxib, and their combination significantly reduced the protein levels of c-Src, Bcl-2, p-AKT, FAK, PGE2, VEGF, and cyclin D1. On the other hand, they elevated active caspase-3. To sum up, Dasatinib/Celecoxib combination increased the capability for apoptosis and suppressed proliferation, angiogenesis, migration, and invasion suggesting a strong cross-talk between Src signaling cascade and COX-2/PGE2 via the intermediate PI3K/AKT/mTOR pathway. Further in-vitro and in-vivo studies are warranted to verify the present findings.

Sign in / Sign up

Export Citation Format

Share Document