scholarly journals Intra-tumoral distribution of Ki-67 and Cyclin D1 in ER+ mammary carcinoma: quantitative evaluation

2021 ◽  
Vol 21 (1) ◽  
pp. 41-6
Author(s):  
Mohammedi Latifa ◽  
Djillali Doula Fatima ◽  
Mesli Farida ◽  
Senhadji Rachid
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Poor Response ◽  
Labeling Index ◽  
Intratumor Heterogeneity ◽  
Cellular Mechanisms ◽  
Ki 67 ◽  
Heterogeneous Distribution ◽  
Er Positive

Background: In spite of the strong evidence demonstrating the role of overexpression of Ki-67 and Cyclin D1 markers in breast carcinomas, clinical and pathological data remain to be discussed. This can be explained partly by intratumor het- erogeneity. Objectives: To define the prevalence and clinical significance of Ki-67 and Cyclin D1 overexpression in primary breast tumors ER positive, while highlighting the existence of intratumor heterogeneity in this type of cancer. Materials and methods: 51 ER positive breast cancer tumors were used to evaluate the intratumoral distribution of Ki-67 and Cyclin D1 expression. Image acquisition and visualization of the markers were performed by optical microscopy and stereology sampling method. Results: The mean Ki-67 labeling index was distributed heterogeneously in the same tumor, from 20.67±6.87 to 45.10±10.65. The coefficient of variation (COV) revealed dispersion values between 13.4% and 42.9%. Associated with positive ER status, all the tumors presented a Cyclin D1 expression with a COV varying between 19% and 28.5% and a mean labeling index fluctuating between 19.40±4.42 and 41.64±10.08 within the same patient showing important intratumor heterogeneous distribution. Conclusion: In this study, we have adopted a strictly quantitative approach to evaluate and demonstrate intratumor hetero- geneity. This establishes one of the main factors for poor response to cancer therapy. To achieve this, intratumor heteroge- neity should be usually definable and quantifiable but this domain awaits future progress and methods need to move towards a better understanding of molecular and cellular mechanisms that initiate and maintain this tumor heterogeneity. Keywords: Breast cancer; Cyclin D1; ER+; Intra-tumoral heterogeneity; Ki-67.

scholarly journals Prognostic significance of Ki-67 labeling index after short-term presurgical tamoxifen in women with ER-positive breast cancer

2011 ◽  
Vol 22 (3) ◽  
pp. 582-587 ◽  
Author(s):  
A. DeCensi ◽  
A. Guerrieri-Gonzaga ◽  
S. Gandini ◽  
D. Serrano ◽  
M. Cazzaniga ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Significance ◽  
Labeling Index ◽  
Short Term ◽  
Ki 67 ◽  
Er Positive ◽  
Positive Breast Cancer

scholarly journals Utility of Ki67 labeling index, cyclin D1 expression, and ER-activity level in postmenopausal ER-positive and HER2-negative breast cancer with neoadjuvant chemo-endocrine therapy

PLoS ONE ◽  
2019 ◽  
Vol 14 (5) ◽  
pp. e0217279 ◽  
Author(s):  
Sasagu Kurozumi ◽  
Yuri Yamaguchi ◽  
Hiroshi Matsumoto ◽  
Masafumi Kurosumi ◽  
Shin-ichi Hayashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Endocrine Therapy ◽  
Activity Level ◽  
Labeling Index ◽  
Ki67 Labeling Index ◽  
Er Positive

Cyclin D1 in Breast Cancer Pathogenesis

2005 ◽  
Vol 23 (18) ◽  
pp. 4215-4224 ◽  
Author(s):  
Andrew Arnold ◽  
Alexandros Papanikolaou
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Great Promise ◽  
Cellular Mechanisms ◽  
Incomplete Knowledge ◽  
Cancer Pathogenesis ◽  
A Cell ◽  
Direct Targeting ◽  
Or Gene

Taking a perspective on available evidence that emphasizes relevance to human disease, cyclin D1 is solidly established as an oncogene with an important pathogenetic role in breast cancer and other human tumors. However, the precise cellular mechanisms through which aberrant cyclin D1 expression drives human neoplasia are less well established. Indeed, emerging evidence suggests that cyclin D1 might act, predominantly or at least in part, through pathways that do not involve its widely accepted function as a cell cycle regulator. Although therapeutic exploitation of the role of cyclin D1 as a molecular driver of breast cancer carries great promise, it is also suggested that direct targeting of the cyclin D1 gene or gene products may prove more successful than approaches that rely on arguably incomplete knowledge of the oncogenic mechanisms of cyclin D1.

Role of Ki67 labeling index (LI) in subdividing homogeneous ER-positive grading groups of early breast cancer (EBC) in distinct biologic entities.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 539-539
Author(s):  
A. Ferro ◽  
M. Barbareschi ◽  
C. Eccher ◽  
A. Caldara ◽  
D. Aldovini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Breast Cancer ◽  
Labeling Index ◽  
Ki67 Labeling Index ◽  
Er Positive

Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E

2005 ◽  
Vol 12 (Supplement_1) ◽  
pp. S47-S59 ◽  
Author(s):  
Alison J Butt ◽  
Catriona M McNeil ◽  
Elizabeth A Musgrove ◽  
Robert L Sutherland
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Endocrine Resistance ◽  
Cycle Progression ◽  
Er Positive ◽  
Oestrogen Signalling

Antioestrogen therapy is a highly effective treatment for patients with oestrogen-receptor (ER)-positive breast cancer, emphasising the central role of oestrogen action in the development and progression of this disease. However, effective antioestrogen treatment is often compromised by acquired endocrine resistance, prompting the need for a greater understanding of the down-stream mediators of oestrogen action that may contribute to this effect. Recent studies have demonstrated a critical link between oestrogen’s mitogenic effects and cell cycle progression, particularly at the G1 to S transition where key effectors of oestrogen action are c-Myc and cyclin D1, which converge on the activation of cyclin E-cdk2. These components are rapidly upregulated in response to oestrogen, and can mimic its actions on cell cycle progression, including re-initiating cell proliferation in antioestrogen-arrested cells. Here we review the roles of c-Myc, cyclin D1 and cyclin E in oestrogen action and endocrine resistance, and identify their potential as markers of disease progression and endocrine responsiveness, and as novel therapeutic targets in endocrine-resistant breast cancer.

scholarly journals Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jun-Xian Du ◽  
Yi-Hong Luo ◽  
Si-Jia Zhang ◽  
Biao Wang ◽  
Cong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
High Risk Group ◽  
Clinical Samples ◽  
Binding Motif ◽  
Ki 67 ◽  
Tissue Samples

Abstract Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

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.

Dantrolene Potentiates the Antineoplastic Effect of Sorafenib in Hepatocellular Carcinoma via Targeting Ca+2/PI3K Signaling Pathway

2021 ◽  
Vol 14 ◽  
Author(s):  
Sherin Zakaria ◽  
Abeer Ansary ◽  
Nabil M. Abdel-Hamid ◽  
Mamdouh M. ElShishtawy
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cyclin D1 ◽  
Antineoplastic Agent ◽  
Inhibitory Effect ◽  
Pi3k Pathway ◽  
Ki 67 ◽  
Antineoplastic Effect ◽  
Pi3k Signaling Pathway ◽  
Proliferation And Metastasis

Background: Hepatocellular carcinoma (HCC) is the 6th prevalent cancer and the 4th leading cause of cancer related deaths all over the world. A major challenge for sorafenib, the standard chemotherapeutic agent in HCC treatment, is the chemo-resistance. Objective: This study was conducted to evaluate the role of dantrolene as a possible antineoplastic agent in HCC, and in chemo-sensitization of sorafenib via targeting Ca+2/PI3K pathway. Methods: HCC was induced in rats using a single dose of diethyl nitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of 18th week, rats were allocated into 4 groups (10 rats/each), one group was left without treatment (DENA group) and the other three groups were treated with either sorafenib, dantrolene, or their combination for further 4 weeks. One day after last injection, serum and liver tissues were collected. Liver tissue p53, VEGF, MMP-9, Cyclin D1, PI3K, and, serum AFP were assessed using immunoassay. Hepatic and serum Ca+2 were also computed. Furthermore, Ki67 was assessed immunohistochemically. Results: Dantrolene exhibited synergistic effect when used in combination with sorafenib compared to either drug alone (p <0.05) through decreasing p53, VEGF, MMP-9, Cyclin D1, and Ki-67. In addition, dantrolene was evidenced to have an inhibitory effect on Ca+2/PI3K pathway that mediates its antineoplastic action when used alone or in combination with sorafenib. Conclusion: Dantrolene exerted antineoplastic effect as well as augmented sorafenib antineoplastic activity via intervention of Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and metastasis.

scholarly journals FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer

2016 ◽  
Vol 113 (43) ◽  
pp. E6600-E6609 ◽  
Author(s):  
Xiaoyong Fu ◽  
Rinath Jeselsohn ◽  
Resel Pereira ◽  
Emporia F. Hollingsworth ◽  
Chad J. Creighton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Cancer Cell Line ◽  
Estrogen Receptor Α ◽  
Resistant Cell ◽  
Transcriptional Reprogramming ◽  
Er Positive ◽  
Integrated Omics ◽  
And Function

Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)–chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.

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