Ki-67 as a prognostic molecular marker in breast cancer

: Immunotherapy emerges as a treatment strategy for breast cancer marker, diagnosis and treatment. In this review, monoclonal antibodies (mAbs)-based passive and peptide vaccines as active immunotherapy approaches like activation of B-cells and T-cells are studied. Passive immunotherapy is mAbs-based therapy effective against tumor cells, which acts by targeting HER2, IGF 1R, VEGF, BCSC and immune checkpoints. Neuropeptide Y (NPY) and GPCR are the areas of interest to target BC metastases for on-targeting therapeutic action. Neuropeptide S (NPS) or NPS receptor 1, acts as a biomarker for Neuroendocrine tumors (NET), mostly characterized by synaptophysin and chromogranin-A expression or Ki-67 proliferation index. The protein fusion technologies arise as a promising avenue in plant expression systems for increased recombinant Ab accumulation and cost-efficient purification. Recently, mAbs-based immunotherapy effectiveness is appreciated as a novel therapeutic combination of chemotherapy and immunotherapy to reduce the side effects and improve therapeutic responsiveness. Synthetic drug resistance will be overcome by mAbs-based therapy through several clinical trials and detection methods need to be optimized for accuracy and precision. Pharmacokinetic attributes need to be accessed for preferred receptor-agonist activity without ligand accumulation.

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AGE FEATURES OF MOLECULAR-BIOLOGICAL SUBTYPES OF BREAST CANCER

Journal of Ural Medical Academic Science ◽

10.22138/2500-0918-2020-17-2-187-192 ◽

2020 ◽

Vol 17 (2) ◽

pp. 187-192

Author(s):

E.A. Novikova ◽

◽

O.V. Kostromina ◽

D.V. Mikhailov ◽

S.L. Leontiev ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Receptors ◽

Age Groups ◽

Luminal A ◽

Ki 67 ◽

Luminal B ◽

Age Related ◽

Age Features ◽

Immunohistochemical Studies ◽

Triple Negative Subtype

Aim. The aim of the study was to determine the presence of peculiarities of the age structure in patients with various surrogate molecular biological subtypes of breast cancer. Materials and research methods. This work analyzes the age-related characteristics of the occurrence of molecular biological subtypes in 499 patients with invasive breast cancer. All cases were divided into 5 molecular biological subtypes based on immunohistochemical studies of hormone receptors, Her2, Ki-67. The average age of the patients was 53.4±0.39 years, the predominant group was patients from 50 to 60 years (37.2% of the total). Research results. In patients under 40 years old, the triple negative subtype prevailed (44.8%). Luminal A subtype prevailed in the groups 51-60 years old (more than 41.4%) and over 60 years old (39.7%). Luminal B (Her2-) subtype was equally found in all age groups.

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Predictive mathematical modelling of recurrence periods for the secondary distant metastases in patients with ER/PR/HER2/Ki-67 subtypes of breast cancer

The Breast ◽

10.1016/s0960-9776(21)00196-x ◽

2021 ◽

Vol 56 ◽

pp. S60-S61

Author(s):

E. Tyuryumina ◽

A. Neznanov ◽

J. Turumin

Keyword(s):

Breast Cancer ◽

Mathematical Modelling ◽

Distant Metastases ◽

Ki 67

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

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01978-8 ◽

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.

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Antitumor effects of Auraptene in 4T1 tumor‐bearing Balb/c mice

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2020-0090 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Mohammad Reza. Shiran ◽

Davar Amani ◽

Abolghasem Ajami ◽

Mahshad Jalalpourroodsari ◽

Maghsoud Khalizadeh ◽

...

Keyword(s):

Breast Cancer ◽

Body Weight ◽

Tumor Volume ◽

Serum Levels ◽

Ki 67 ◽

Tumor Bearing ◽

Paraffin Oil ◽

Anti Cancer ◽

Before And After ◽

Ifn Γ

Abstract Objectives Breast cancer is a common malignant tumor in women with limited treatment options and multiple side effects. Today, the anti-cancer properties of natural compounds have attracted widespread attention from researchers worldwide. Methods In this study, we treated 4T1 tumor-bearing Balb/c mice with intraperitoneal injection of Auraptene, paraffin oil, and saline as two control groups. Body weight and tumor volume were measured before and after treatment. Hematoxylin and eosin (H & E) staining and immunohistochemistry of Ki-67 were used as markers of proliferation. In addition, ELISA assays were performed to assess serum IFN-γ and IL-4 levels. Results There was no significant change in body weight in all animal groups before and after treatment. 10 days after the last treatment, Auraptene showed its anti-cancer effect, which was confirmed by the smaller tumor volume and H & E staining. In addition, Ki-67 expression levels were significantly reduced in tumor samples from the Auraptene-treated group compared to the paraffin oil and saline-treated groups. In addition, in tumor-bearing and normal mice receiving Auraptene treatment, IL-4 serum production levels were reduced, while serum levels of IFN-γ were significantly up-regulated in tumor-bearing mice after Auraptene treatment. Conclusions In the case of inhibition of tumor volume and Ki-67 proliferation markers, Auraptene can effectively inhibit tumor growth in breast cancer animal models. In addition, it might increases Th1 and CD8 + T cell responses after reducing IL-4 serum levels and IFN-γ upregulation, respectively. However, further research is needed to clarify its mechanism of action.

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SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01933-7 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Qiao Li ◽

Manran Liu ◽

Yan Sun ◽

Ting Jin ◽

Pengpeng Zhu ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Histological Grade ◽

Metabolic Adaptation ◽

Mitochondrial Activity ◽

Cell Viability Assay ◽

Ki 67 ◽

The Impact

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

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