Gene Summary

Gene:MKI67; marker of proliferation Ki-67
Aliases: KIA, MIB-, MIB-1, PPP1R105
Summary:This gene encodes a nuclear protein that is associated with and may be necessary for cellular proliferation. Alternatively spliced transcript variants have been described. A related pseudogene exists on chromosome X. [provided by RefSeq, Mar 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:proliferation marker protein Ki-67; antigen KI-67
Source:NCBIAccessed: 14 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 14 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 14 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MKI67 (cancer-related)

Demerath T, Simon-Gabriel CP, Kellner E, et al.
Mesoscopic imaging of glioblastomas: Are diffusion, perfusion and spectroscopic measures influenced by the radiogenetic phenotype?
Neuroradiol J. 2017; 30(1):36-47 [PubMed] Related Publications
The purpose of this study was to identify markers from perfusion, diffusion, and chemical shift imaging in glioblastomas (GBMs) and to correlate them with genetically determined and previously published patterns of structural magnetic resonance (MR) imaging. Twenty-six patients (mean age 60 years, 13 female) with GBM were investigated. Imaging consisted of native and contrast-enhanced 3D data, perfusion, diffusion, and spectroscopic imaging. In the presence of minor necrosis, cerebral blood volume (CBV) was higher (median ± SD, 2.23% ± 0.93) than in pronounced necrosis (1.02% ± 0.71), pcorr = 0.0003. CBV adjacent to peritumoral fluid-attenuated inversion recovery (FLAIR) hyperintensity was lower in edema (1.72% ± 0.31) than in infiltration (1.91% ± 0.35), pcorr = 0.039. Axial diffusivity adjacent to peritumoral FLAIR hyperintensity was lower in severe mass effect (1.08*10(-3) mm(2)/s ± 0.08) than in mild mass effect (1.14*10(-3) mm(2)/s ± 0.06), pcorr = 0.048. Myo-inositol was positively correlated with a marker for mitosis (Ki-67) in contrast-enhancing tumor, r = 0.5, pcorr = 0.0002. Changed CBV and axial diffusivity, even outside FLAIR hyperintensity, in adjacent normal-appearing matter can be discussed as to be related to angiogenesis pathways and to activated proliferation genes. The correlation between myo-inositol and Ki-67 might be attributed to its binding to cell surface receptors regulating tumorous proliferation of astrocytic cells.

Chen SW, Lin YC, Chen RY, et al.
Immunohistochemical overexpression of hypoxia-induced factor 1α associated with slow reduction in (18)fluoro-2-deoxy-D-glucose uptake for chemoradiotherapy in patients with pharyngeal cancer.
Eur J Nucl Med Mol Imaging. 2016; 43(13):2343-2352 [PubMed] Related Publications
BACKGROUND: This study examined genomic factors associated with a reduction in (18)fluoro-2-deoxy-D-glucose (FDG) uptake during positron emission tomography-computed tomography (PET-CT) for definitive chemoradiotherapy (CRT) in patients with pharyngeal cancer.
METHODS: The pretreatment and interim PET-CT images of 25 patients with advanced pharyngeal cancers receiving definitive CRT were prospectively evaluated. The maximum standardized uptake value (SUVmax) of the interim PET-CT and the reduction ratio of the SUVmax (SRR) between the two images were measured. Genomic data from pretreatment incisional biopsy specimens (SLC2A1, CAIX, VEGF, HIF1A, BCL2, Claudin-4, YAP1, MET, MKI67, and EGFR) were analyzed using tissue microarrays. Differences in FDG uptake and SRRs between tumors with low and high gene expression were examined using the Mann-Whitney test. Cox regression analysis was performed to examine the effects of variables on local control.
RESULTS: The SRR of the primary tumors (SRR-P) was 0.59 ± 0.31, whereas the SRR of metastatic lymph nodes (SRR-N) was 0.54 ± 0.32. Overexpression of HIF1A was associated with a high iSUVmax of the primary tumor (P < 0.001) and neck lymph node (P = 0.04) and a low SRR-P (P = 0.02). Multivariate analysis revealed that patients who had tumors with low SRR-P or high HIF1A expression levels showed inferior local control.
CONCLUSION: In patients with pharyngeal cancer requiring CRT, HIF1A overexpression was positively associated with high interim SUVmax or a slow reduction in FDG uptake. Prospective trials are needed to determine whether the local control rate can be stratified using the HIF1A level as a biomarker and SRR-P.

Guo S, Bai Q, Rohr J, et al.
Clinicopathological features of primary diffuse large B-cell lymphoma of the central nervous system - strong EZH2 expression implying diagnostic and therapeutic implication.
APMIS. 2016; 124(12):1054-1062 [PubMed] Related Publications
Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a rare entity which is difficult to diagnose and treat. The histone methyltransferase EZH2 was reported to be involved in the tumorigenesis of systemic DLBCL but has not been implicated in primary CNS DLBCL. The clinicopathological features of 33 cases of primary CNS DLBCL and expression of EZH2 and Y641 mutation were assessed. The tumor cells of the majority cases resembled centroblasts, and intriguingly, three cases of rare anaplastic variant were observed. Immunophenotypically, 25/33 (75.8%) cases were non-germinal center B-cell-like type. Several cases (10/33; 30.3%) co-expressed BCL2 and MYC, 6/33 (18.2%) expressed both BCL6 and MYC, and 5/33 (15.2%) expressed BCL2, BCL6, and MYC. MYC expression alone and BCL2/MYC co-expression were associated with poor prognosis. EZH2 was strongly expressed in all 33 cases independent of Y641 mutation and was significantly associated with the tumor proliferative index Ki67. However, no association was found between the level of EZH2 expression and outcomes of patients. In summary, the clinicopathological features including three rare anaplastic variant of primary CNS DLBCL are described. Strong expression of EZH2 in all the primary CNS DLBCL and association with high proliferative index provides further information for treatment and diagnosis of this distinctive entity.

Breyer J, Wirtz RM, Laible M, et al.
ESR1, ERBB2, and Ki67 mRNA expression predicts stage and grade of non-muscle-invasive bladder carcinoma (NMIBC).
Virchows Arch. 2016; 469(5):547-552 [PubMed] Related Publications
Pathological staging and grading are crucial for risk assessment in non-muscle-invasive bladder cancer (NMIBC). Molecular grading might support pathological evaluation and minimize interobserver variability. In this study, the well-established breast cancer markers ESR1, PGR, ERBB2, and MKI67 were evaluated as potential molecular markers to support grading and staging in NMIBC. We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with NMIBC. Messenger RNA (mRNA) expression of the aforementioned markers was measured by single-step reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) using RNA-specific TaqMan assays. Relative gene expression was determined by normalization to two reference genes (CALM2 and B2M) using the 40(-ΔΔCT) method and correlated to histopathological stage and grade. Pathological assessment was performed by an experienced uropathologist. Statistical analysis was performed using the SAS software JMP 9.0.0 version and GraphPad Prism 5.04. Of 381 cases of NMIBC, samples of 100 pTa and 255 pT1 cases were included in the final study. Spearman rank correlation revealed significant correlations between grade and expression of MKI67 (r = 0.52, p < 0.0001), ESR1 (r = 0.25, p < 0.0001), and ERBB2 (r = 0.18, p = 0.0008). In Mann-Whitney tests, MKI67 was significantly different between all grades (p < 0.0001), while ESR1 (p = 0.0006) and ERBB2 (p = 0.027) were significantly different between G2 and G3. Higher expression of MKI67 (r = 0.49; p < 0.0001), ERBB2 (r = 0.22; p < 0.0001), and ESR1 (r = 0.18; p = 0.0009) mRNA was positively correlated with higher stage. MKI67 (p < 0.0001), ERBB2 (p = 0.0058), and PGR (p = 0.0007) were significantly different between pTa and pT1. In NMIBC expression of ESR1, ERBB2 and MKI67 are significantly different between stage and grade. This potentially provides objective parameters for pathological evaluation.

Manjili MH, Butler SE
Role of Tregs in Cancer Dormancy or Recurrence.
Immunol Invest. 2016; 45(8):759-766 [PubMed] Related Publications
The immunogenic tumor dormancy has been demonstrated in animal models of cancer, which can explain clinical observations such as an increased incidence of cancer following organ transplantation. The role of immune cell populations in the maintenance of, or escape from, tumor dormancy and subsequent recurrence is poorly understood. Here, we provide a review of literature related to the contribution of Tregs in tumor dormancy or recurrence. Based on clinical results, we suggest that anecdotal reports on the association of human Tregs with poor prognosis are circumstantial rather than implying a cause-effect direction. This could be due to a disparity among patients in harboring multiple factors associated with tumor immunoediting and immune evasion mechanisms.

Li J, Song ZJ, Wang YY, et al.
Low levels of serum miR-99a is a predictor of poor prognosis in breast cancer.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
MicroRNA (miRNA) deregulation has been previously linked to the initiation and development of breast cancer. Although miR-99a is aberrantly expressed in many types of cancers, including breast cancer, the serum miR-99a expression level in breast cancer and its clinical significance remains unknown. Blood samples were obtained from 72 patients with breast cancer and 40 healthy volunteers, and subjected to real-time polymerase chain reaction to evaluate the level of expression of serum miR-99a in the study participants. Furthermore, we investigated the association between serum miR-99a and the clinical outcome of breast cancer. Serum miR-99a expression was significantly downregulated in patients with breast cancer, compared to that in healthy controls (P < 0.01). Moreover, the serum miR-99a was correlated with various clinical parameters of breast cancer, including lymph node metastasis (P = 0.0194), distant metastasis (P = 0.0037), Ki67 intensity (P = 0.0164), TNM stage (P = 0.0096), and histological grade (P = 0.0051) of cancer. Additionally, breast cancer patients displaying lower miR-99a levels showed poorer overall survival rates (P = 0.0411). The serum miR-99a level was also found to be an independent risk factor for breast cancer (hazard ratio = 3.176, 95% confidence interval = 1.543-7.360, P = 0.023). Our data indicated that serum miR-99a expression was downregulated in breast cancer patients; moreover, this downregulation was associated with poor prognosis, suggesting that serum miR-99a could function as a tumor suppressor in breast cancer.

Zuo HD, Wu Yao W
The role and the potential regulatory pathways of high expression of forkhead box C1 in promoting tumor growth and metastasis of basal-like breast cancer.
J BUON. 2016 Jul-Aug; 21(4):818-825 [PubMed] Related Publications
PURPOSE: To investigate the role of high forkhead box C1 (FOXC1) expression in basal-like breast cancer (BLBC) in vitro and vivo and the underlying regulatory mechanism.
METHODS: The lentivirus vector with green fluorescent protein (GFP) was used. MDA-MB-231 cells expressing consistently high levels of FOXC1 (FOXC1-MDA-MB-231) were established. The parental MDA-MB-231 cells served as controls. Western blot analysis was used to determine the FOXC1 expression. The invasion capability was tested using the Trans-well assay. The tumorigenicity and the pulmonary metastatic ability were determined in mice in vivo. Histopathology and microarray processing and analysis were performed, and the various pathways involved and the related genes were analyzed.
RESULTS: The invasion ability of FOXC1-MDA-MB-231 cells was enhanced significantly (p<0.01). Pulmonary metastases were observed in vivo in 3 of 5 mice administered FOXC1-MDA-MB-231 cells through tail vein injection. However, no pulmonary metastatic lesions were observed with MDA-MB-231 cells. The average tumor volume was larger in the mice injected with FOXC1-MDA-MB-231 than in the control mice (p<0.05). The expression of Ki-67 in the FOXC1-MDA-MB-231 injected mice was higher than in the control mice. Ten of the most gene-enriched pathways and the critical genes (IL-6 and SNAI2) were found to be related to BLBC.
CONCLUSION: Elevated expression of FOXC1 enhanced the invasion ability of BLCB cells in vitro and promoted tumor growth and metastatic ability in vivo. This function may be regulated by many gene-enriched pathways and some critical genes.

DA Cruz Paula A, Marques O, Sampaio R, et al.
Characterization of CD44+ALDH1+Ki-67- Cells in Non-malignant and Neoplastic Lesions of the Breast.
Anticancer Res. 2016; 36(9):4629-38 [PubMed] Related Publications
BACKGROUND: Cancer stem cells are tumor cells that present self-renewal, clonal tumor initiation capacity and clonal long-term repopulation potential. We have previously demonstrated that the co-expression of the breast cancer stem cell (BCSC) markers hyaluronan receptor (CD44) and aldehyde dehydrogenase-1 (ALDH1) in ductal carcinomas in situ could be determinant for disease progression. Combining these established BCSC markers with Ki-67 to evaluate quiescence we sought to identify, evaluate the distribution and estimate the mean percentages of CD44(+)ALDH1(+)Ki-67(-) breast cells.
MATERIALS AND METHODS: Triple-immunohistochemistry for CD44, ALDH1 and Ki-67 was applied in a series of 16 normal, 54 non-malignant and 155 malignant breast tissues. Clinical relevance was inferred by associations with markers of breast cancer behavior, progression and survival.
RESULTS: The mean percentages of cells with this phenotype increased significantly from non-malignant lesions to high-grade ductal carcinomas in situ, decreasing in invasive ductal carcinomas, as also evidenced by an inverse correlation with histological grade and tumor size. The mean percentage of CD44(+)ALDH1(+)Ki-67(-) cells was also significantly higher in women who developed distant metastasis and died due to breast cancer, and a significant association with human epidermal growth factor type 2 (HER2) negativity was observed.
CONCLUSION: Our novel findings indicate that CD44(+)ALDH1(+)Ki-67(-) tumor cells may favor distant metastasis and can predict overall survival in patients with ductal carcinomas of the breast. More importantly, quiescence may have a crucial role for tumor progression, treatment resistance and metastatic ability of BCSCs.

Besusparis J, Plancoulaine B, Rasmusson A, et al.
Impact of tissue sampling on accuracy of Ki67 immunohistochemistry evaluation in breast cancer.
Diagn Pathol. 2016; 11(1):82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene expression studies have identified molecular subtypes of breast cancer with implications to chemotherapy recommendations. For distinction of these types, a combination of immunohistochemistry (IHC) markers, including proliferative activity of tumor cells, estimated by Ki67 labeling index is used. Clinical studies are frequently based on IHC performed on tissue microarrays (TMA) with variable tissue sampling. This raises the need for evidence-based sampling criteria for individual IHC biomarker studies. We present a novel tissue sampling simulation model and demonstrate its application on Ki67 assessment in breast cancer tissue taking intratumoral heterogeneity into account.
METHODS: Whole slide images (WSI) of 297 breast cancer sections, immunohistochemically stained for Ki67, were subjected to digital image analysis (DIA). Percentage of tumor cells stained for Ki67 was computed for hexagonal tiles super-imposed on the WSI. From this, intratumoral Ki67 heterogeneity indicators (Haralick's entropy values) were extracted and used to dichotomize the tumors into homogeneous and heterogeneous subsets. Simulations with random selection of hexagons, equivalent to 0.75 mm circular diameter TMA cores, were performed. The tissue sampling requirements were investigated in relation to tumor heterogeneity using linear regression and extended error analysis.
RESULTS: The sampling requirements were dependent on the heterogeneity of the biomarker expression. To achieve a coefficient error of 10 %, 5-6 cores were needed for homogeneous cases, 11-12 cores for heterogeneous cases; in mixed tumor population 8 TMA cores were required. Similarly, to achieve the same accuracy, approximately 4,000 nuclei must be counted when the intratumor heterogeneity is mixed/unknown. Tumors of low proliferative activity would require larger sampling (10-12 TMA cores, or 6,250 nuclei) to achieve the same error measurement results as for highly proliferative tumors.
CONCLUSIONS: Our data show that optimal tissue sampling for IHC biomarker evaluation is dependent on the heterogeneity of the tissue under study and needs to be determined on a per use basis. We propose a method that can be applied to determine the sampling strategy for specific biomarkers, tissues and study targets. In addition, our findings highlight the benefit of high-capacity computer-based IHC measurement techniques to improve accuracy of the testing.

Tang P, Tse GM
Immunohistochemical Surrogates for Molecular Classification of Breast Carcinoma: A 2015 Update.
Arch Pathol Lab Med. 2016; 140(8):806-14 [PubMed] Related Publications
CONTEXT: -The pioneering works on molecular classification (MC) by Perou and Sorlie et al in the early 2000s using global gene expression profiling identified 5 intrinsic subtypes of invasive breast cancers (IBCs): luminal A, luminal B, normal breast-like, HER2-enriched, and basal-like subtypes, each unique in incidence, survival, and response to therapy. Because the application of gene expression profiling in daily practice is not economical or practical at the present time, many investigators have studied the use of immunohistochemical (IHC) surrogates as a substitute for determining the MC of IBC.
OBJECTIVE: -To discuss the continuing efforts that have been made to develop clinically significant and readily available IHC surrogates for the MC of IBC.
DATA SOURCES: -Data were obtained from pertinent peer-reviewed English-language literature.
CONCLUSIONS: -The most commonly used IHC surrogates are estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), dividing IBC into luminal, HER2, and triple-negative subtypes. The addition of Ki-67, cytokeratin 5, and epidermal growth factor receptor (EGFR) separates luminal B from luminal A subtypes, and basal-like subtype from triple-negative breast cancer. More recently, biomarkers such as androgen receptor and p53 have been shown to further stratify these molecular subtypes. Although many studies of IHC-based MC have shown clinical significance similar to gene expression profiling-defined MC, its critical limitations are: (1) a lack of standardization in terminology, (2) a lack of standardization in biomarkers used for each subtype, and (3) the lack of a uniform cutoff for each biomarker. A panel of IHC surrogates for each subtype of IBC is proposed.

Zatonski T, Ciesielska U, Nowinska K, et al.
Expression of Cell Cycle-Related Proteins p16, p27, p53 and Ki-67 in HPV-positive and -negative Samples of Papillomas of the Upper Respiratory Tract.
Anticancer Res. 2016; 36(8):3917-24 [PubMed] Related Publications
BACKGROUND: The role of human papillomavirus (HPV) infection as an etiological factor of respiratory tract papillomas has been described in numerous studies, however its role in malignant transformation has not been clearly defined. Depending on their oncogenic potential they have been classified as low- and high-risk HPVs. We analyzed the expression of four cell cycle-related proteins in order to understand the processes leading to malignant transformation.
MATERIALS AND METHODS: Fifty-six cases of pharyngeal and laryngeal papillomas were analyzed. Nested multiplex polymerase chain reactions to detect the presence of the HPV types, as well as immunohistochemical reactions were performed for the detection of cell cycle-related proteins p16, p27, p53 and Ki-67.
RESULTS: The presence of HPVs 6/11 and 16 was confirmed in 10/56 cases. The expression of all analyzed cell cycle-related proteins was increased in HPV-infected papillomas.
CONCLUSION: HPV infection of the upper respiratory tract may influence the expression of cell cycle-related proteins, that could indicate its possible role in the process of malignant transformation.

Qaiser F, Trembley JH, Sadiq S, et al.
Examination of CK2α and NF-κB p65 expression in human benign prostatic hyperplasia and prostate cancer tissues.
Mol Cell Biochem. 2016; 420(1-2):43-51 [PubMed] Related Publications
Protein kinase CK2 plays a critical role in cell growth, proliferation, and suppression of cell death. CK2 is overexpressed, especially in the nuclear compartment, in the majority of cancers, including prostate cancer (PCa). CK2-mediated activation of transcription factor nuclear factor kappa B (NF-κB) p65 is a key step in cellular proliferation, resulting in translocation of NF-κB p65 from the cytoplasm to the nucleus. As CK2 expression and activity are also elevated in benign prostatic hyperplasia (BPH), we sought to increase the knowledge of CK2 function in benign and malignant prostate by examination of the relationships between nuclear CK2 and nuclear NF-κB p65 protein expression. The expression level and localization of CK2α and NF-κB p65 proteins in PCa and BPH tissue specimens was determined. Nuclear CK2α and NF-κB p65 protein levels are significantly higher in PCa compared with BPH, and these proteins are positively correlated with each other in both diseases. Nuclear NF-κB p65 levels correlated with Ki-67 or with cytoplasmic NF-κB p65 expression in BPH, but not in PCa. The findings provide information that combined analysis of CK2α and NF-κB p65 expression in prostate specimens relates to the disease status. Increased nuclear NF-κB p65 expression levels in PCa specifically related to nuclear CK2α levels, indicating a possible CK2-dependent relationship in malignancy. In contrast, nuclear NF-κB p65 protein levels related to both Ki-67 and cytoplasmic NF-κB p65 levels exclusively in BPH, suggesting a potential separate impact for NF-κB p65 function in proliferation for benign disease as opposed to malignant disease.

Veneroni S, Dugo M, Daidone MG, et al.
Applicability of Under Vacuum Fresh Tissue Sealing and Cooling to Omics Analysis of Tumor Tissues.
Biopreserv Biobank. 2016; 14(6):480-490 [PubMed] Related Publications
CONTEXT: Biobanks of frozen human normal and malignant tissues represent a valuable source for "omics" analysis in translational cancer research and molecular pathology. However, the success of molecular and cellular analysis strongly relies on the collection, handling, storage procedures, and quality control of fresh human tissue samples.
OBJECTIVE: We tested whether under vacuum storage (UVS) effectively preserves tissues during the time between surgery and storage for "omics" analyses.
DESIGN: Normal and matched tumor specimens, obtained from 16 breast, colon, or lung cancer patients and 5 independent mesenchymal tumors, were dissected within 20 minutes from surgical excision and divided in three to five aliquots; for each tissue sample, one aliquot was snap-frozen in liquid nitrogen (defined as baseline or T0 samples), and the other portions were sealed into plastic bags and kept at 4°C for 1, 24, 48, or 72 hours under vacuum and then frozen. The tissue and molecular preservation under vacuum was evaluated over time in terms of histomorphology, transcription (Illumina microarrays), protein (surface-enhanced laser desorption/ionization-time of flight/mass spectrometry and Western blot), and metabolic profile (nuclear magnetic resonance spectroscopy).
RESULTS: Tissue morphology, Mib-1, and vimentin immunostaining were preserved over time without signs of tissue degradation. Principal variance component analysis showed that time of storage had a minimal effect on gene expression or the proteome, but affected the preservation of some metabolites to a greater extent. UVS did not impact the RNA and protein integrity or specific phosphorylation sites on mTOR and STAT3. Measurement of metabolites revealed pronounced changes after 1 hour of storage.
CONCLUSIONS: Our results show that UVS can preserve tissue specimens for histological, transcriptomic, and proteomic examinations up to 48 hours and possibly longer, whereas it has limitations for metabolomic applications.

Miralpeix E, Solé-Sedeño JM, Mancebo G, et al.
Value of p16(INK4a) and Ki-67 Immunohistochemical Staining in Cervical Intraepithelial Neoplasia Grade 2 Biopsies as Biomarkers for Cervical Intraepithelial Neoplasia Grade 3 in Cone Results.
Anal Quant Cytopathol Histpathol. 2016; 38(1):1-8 [PubMed] Related Publications
OBJECTIVE: To evaluate the usefulness of p16(INK4a) (p16) and Ki-67 staining in high-grade cervical intraepithelial neoplasia (CIN2) biopsies in order to predict CIN3 results in cone specimens, thereby sparing those not likely at risk for CIN3 from unnecessary cone excision.
STUDY DESIGN: We retrospectively recruited patients with CIN2 colposcopy-directed biopsy treated by loop electrosurgical excision procedure. The expression of p16 and Ki-67 was qualitatively and quantitatively analyzed in all biopsies and cone specimens.
RESULTS: A total of 123 patients from January 2009 to December 2010 were included in the study. CIN3 in cone specimens was observed in 35 patients (28.5%). Ki-67 positive immunostaining in > 50% of epithelial cells was related to CIN3 diagnoses in cone specimens (p = 0.043). However, p16+ and Ki-67+ evaluated by thirds of the epithelial thickness in CIN2 biopsies did not show a significant correlation with the cone results. In multivariate analysis, Ki-67 cell expression over 50% in CIN2 biopsies and high-grade squamous intraepithelial lesion (HSIL) in the previous cytology were statistically associated with CIN3 results in the cone (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.04-6.29; OR 2.68, 95% CI 1.07-6.72, respectively).
CONCLUSION: Patients with HSIL in the previous cytology and Ki-67 cell expression over 50% in their CIN2 biopsies could be considered in need of treatment by cone for their higher risk of underlying CIN3 lesions.

Leijon H, Salmenkivi K, Heiskanen I, et al.
HuR in pheochromocytomas and paragangliomas - overexpression in verified malignant tumors.
APMIS. 2016; 124(9):757-63 [PubMed] Related Publications
Pheochromocytomas and paragangliomas are rare, neural crest-originating, neuroendocrine tumors. HuR is an mRNA-binding protein of the ELAV/Hu-protein family, which participates in posttranscriptional regulation of many cancer-associated genes. HuR expression has been connected with aggressive behavior of several malignancies. Cyclooxygenase-2 (COX-2) is also expressed in several malignant tumors, and its expression is regulated by HuR. Tissue microarray of 153 primary pheochromocytomas and paragangliomas was investigated for the expression of HuR and COX-2 proteins by immunohistochemistry using two different HuR antibodies (HuR19F12 and HuR3A). In these tumors, the expression of both intranuclear and cytoplasmic HuR was detectable. Increased cytoplasmic HuR expression was significantly associated with metastatic tumors. Increased COX-2 and MIB-1 expression also was associated with metastatic potential, and moreover, HuR and COX-2 expression correlated with each other. Our data suggest that increased expression of HuR protein is associated with metastatic potential of paragangliomas and pheochromocytomas, and COX-2 seems to be a target of HuR.

Nowakowska M, Matysiak-Burzyńska Z, Kowalska K, et al.
Angiotensin II promotes endometrial cancer cell survival.
Oncol Rep. 2016; 36(2):1101-10 [PubMed] Related Publications
Endometrial cancer (EC) is one of the most common female cancers. One of the key processes involved in EC development is uncontrolled proliferation stimulated by local factors such as angiotensin. The aim of the present study was to evaluate the influence of angiotensin II (Ang II) on human EC cells. Biological assays and gene expression analysis were performed on three cell lines: ISH, MFE-296 and MFE-280. Our results indicated that at the beginning of cancerogenesis Ang II induced abnormal proliferation at lower doses. We also showed that dose-dependent induction of proliferation was connected with changes in the expression of MKI67, CCND1 and CCNE1 genes in well- and poorly differentiated cancer cells. After Ang II treatment, poorly differentiated endometrial cancer cell line acquired a mesenchymal phenotype, which was characterized by induced expression of EMT-related genes (VIM, CD44, SNAI1, ZEB1 and ZEB2). Our study revealed that Ang II influences EC cells in terms of cancer-related processes, and is responsible for increased proliferation, reduction in apoptosis, increased mobility and modulation of adhesion potential. Its effect and effectiveness appear to be highly connected with the differentiation status of the cancerous cells, as Ang II appears to play a crucial role in the early and late stages of malignant transformation.

Curigliano G, Gómez Pardo P, Meric-Bernstam F, et al.
Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study.
Breast. 2016; 28:191-8 [PubMed] Related Publications
OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting.
MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling.
RESULTS: Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment.
CONCLUSION: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).

Zhao G, Ge T, Yang X, Li X
The direct anti-cancer efficacy of Sapylin on breast cancer cells in vitro and in vivo.
Hell J Nucl Med. 2016 May-Aug; 19(2):111-7 [PubMed] Related Publications
OBJECTIVE: On the basis of our previous study in which we studied cancer cells under in vitro and in vivo hypoxia conditions, we have now investigated the anti-cancer efficacy of Sapylin on breast cancer cells in mice and human.
MATERIALS AND METHODS: We used different concentrations of Sapylin and the three kinds of breast cancer cells. We used water-soluble tetrazolium salt cell proliferation test (WST-1) to detect changes in cell proliferation and Fluorescein Iothiocyanate-Propidium Iodide (Anexin V FITC-PI) to detect changes in the rate of apoptosis by flow cytometry. We also used reverse transcription-polymerase chain reaction (RT-PCR) to detect possible changes of mRNA expression and used western blot in order to test changes related to protein expression that could lead to cell death. The anti-tumor effect was studied by locally injecting Sapylin into an animal tumor model of breast cancer. We also studied the possible postoperative adverse clinical side effects in 60 female breast cancer patients, stage II-III, aged 25-55 years. The patients underwent a modified, radical operation with smooth incisions which healed well.
RESULTS: Sapylin was able to inhibit by 10%-15% the proliferation of all three kinds of breast cancer cells and also to present positive correlation in vivo with some phenomenona which were time and concentration dependent. After applying Sapylin for 48h, the apoptosis rate was significantly increased by 12%-20%. Apoptosis of breast cancer cells may be related to biological effects supporting cells survival, through B-cell lymphoma gene 2 (Bcl-2nd) Ki67 mRNA expression descent and Bcl-2 associated X Protein (Bax mRNA) expression. This process ultimately promotes cell death. At the same time this process also showed a significant anti-tumor effect (50%-60%) in a mice model. We found no significant adverse reactions, the patients had no significant pain and the postoperative wound was partially healed. After 5 days, the drainage was well reduced and remained so more in the study group than in the control group at a range of 20%-30% (P<0.05).
CONCLUSION: In our research, Sapylin displayed a strong direct anti-cancer effect in breast cancer cells and supported postoperative recovery. Clinically we noticed an obvious reduction of drainage in contrast with the control group.

Kölbl AC, Bräuer D, Hutter S, et al.
New Marker Genes for Real-Time PCR-based Detection of Circulating Tumour Cells from Blood of Breast Cancer Patients.
Anticancer Res. 2016; 36(6):3211-6 [PubMed] Related Publications
BACKGROUND: The detection of circulating tumour cells (CTCs) from peripheral blood of cancer patients can be carried out by real-time PCR approaches using different gene expression levels of tumour cells and surrounding blood cells.
MATERIALS AND METHODS: Potential marker genes were first analyzed in a model system and then applied to 20 blood samples of adjuvant breast cancer patients and gene expression levels were correlated to tumour characteristics.
RESULTS: The mean of gene expression levels was found elevated for the four genes analyzed in the adjuvant breast cancer patient group in comparison to the samples of the group of healthy donors, but no correlation between gene expression and tumour characteristics could be detected as being statistically significant.
CONCLUSION: The results demonstrated, that the employed methodology is functional, but has to be refined by certain approaches like simultaneously running a state-of-the-art system of CTC-detection comparing the results, and by an enlargement of patient collective and number of marker genes.

Thomas C, Robinson C, Dessauvagie B, et al.
Expression of proliferation genes in formalin-fixed paraffin-embedded (FFPE) tissue from breast carcinomas. Feasibility and relevance for a routine histopathology laboratory.
J Clin Pathol. 2017; 70(1):25-32 [PubMed] Related Publications
AIM: Breast carcinoma proliferative activity, histological grade and commercial molecular tests are all important in prognostication and treatment. There is a particular need for improved, standardised techniques for subclassification of grade 2 breast cancers into low-risk and high-risk prognostic groups. In this study we investigated whether gene expression profiling of five proliferation genes was feasible using breast cancer tissue in a clinical setting and whether these profiles could enhance pathological assessment.
METHODS: Expression of five proliferation gene mRNAs; Ki-67, STK 15, CCNB1, CCND1 and MYBL2, was quantified in 27 breast carcinomas and compared with Ki-67 proliferation index (PI) and Nottingham mitotic score.
RESULTS: Expression of Ki-67, STK15 and MYBL2 mRNA showed moderate Spearman's correlation with Ki-67 PI (p<0.01), but CCND1 and CCNB1 showed weak, non-significant correlation. Individual gene expression did not associate with mitotic score but combined mRNA expression correlated with both Ki-67 PI (p=0.018) and mitotic score (p=0.03; 0.007).
CONCLUSIONS: This study confirms mRNA analysis in breast carcinoma formalin-fixed, paraffin-embedded samples is feasible and suggests gene expression profiling, using a small set of five proliferation genes, has potential in aiding histological grading or assessment of proliferative activity of breast cancers. To fully evaluate the clinical applicability of this approach, a larger cohort study with long-term follow-up data is required.

Wierzbicka-Tutka I, Sokołowski G, Bałdys-Waligórska A, et al.
PTTG and Ki-67 expression in pituitary adenomas.
Przegl Lek. 2016; 73(2):53-8 [PubMed] Related Publications
INTRODUCTION: The unpredictable biology of pituitary adenomas makes it a therapeutic challenge. Moreover ,histopathology of pituitary carcinomas and locally invasive adenomas are indistinguishable from benign tumors and a new marker which would enable to differentiate those lesions is vital. The aim of the study was to evaluate Ki-67 and PTTG (pituitary tumour--transforming gene) expression in pituitary adenomas and their applicationas markers of tumour aggressiveness.
MATERIAL AND METHODS: A retrospective analysis of 55 patients: 32 females(58%) and 23 males (42%), mean age 50 ± 16 years who underwent pituitary tumor surgery between 2003-2012. Ki-67 and PTTG indices were determined by immunohistochemical staining. Magnetic resonance imaging or computed tomography was performed beforehand and one year after surgery to figure a potential tumour progression, tumour size and correlation to adjacent tissues.
RESULTS: The expression of Ki-67and PTTG was revealed in cell nucleiin 88% and 85% of adenomas, respectively. The median Ki-67 and PTTG indices were 1.4 and 1.0, respectively(p = 0.006). In the group with macroadenoma as compared with the group with microadenoma, median Ki-67 index was higher (1.4% vs. 1.03%; p = 0.02). We did not find correlation between both Ki-67 and PTTG indices and tumour progression. Tumours with positive immunostaining towards FSH revealed lower Ki-67 and PTTG indices than the rest with a negative one (0.6% vs.1.84%, p = 0.0004 and 0.67% vs 1.23%,p = 0.047; respectively). However, PTTG index was higher in the group with acromegaly as compared to the group with clinically non-functioning pituitary adenoma (NFPA) (1.28% vs.0.35%; p = 0.02).
CONCLUSIONS: Positive nuclear expression of Ki-67 and PTTG was observed in the majority of pituitary adenomas. Only higher Ki-67 expression was related to the tumour invasiveness found on MRI/CT. Tumour progressionwas not related to both Ki-67 and PTTG expression.

Park SY, Bae JS, Cha EJ, et al.
Nuclear EpICD expression and its role in hepatocellular carcinoma.
Oncol Rep. 2016; 36(1):197-204 [PubMed] Related Publications
Regulated intramembrane proteolysis of epithelial cell adhesion molecule (EpCAM) results in shedding of the extracellular domain (EpEX) and release of the intra-cellular domain (EpICD) into the cytoplasm. Released EpICD associates with FHL2, β-catenin and Lef-1 to form a nuclear complex and triggers oncogenic signaling. This study was conducted to examine the nuclear expression of EpICD in hepatocellular carcinoma (HCC) and to assess the role of EpICD in HCC. EpICD immunoexpression was examined in 100 cases of HCC using tissue microarrays and correlated with clinicopathological parameters. We also examined the role of EpICD in HCC using EpICD cDNA transfected HCC cell line and EpCAM silenced HCC cell line by small interfering RNA (siRNA). Nuclear expression of EpICD was observed in 19 of 100 (19%) cases. Nuclear expression of EpICD significantly correlated with nuclear expression of β-catenin, and Ki-67 labeling index. In addition, nuclear expression of EpICD was associated with higher histologic grade and advanced T category. Forced overexpression of EpICD in the HCC cell significantly increased the cell proliferation, migration and invasion. The overexpression of EpICD also increased the expression levels of the active form of β-catenin and c-myc and cyclin D1. In contrast, downregulation of EpCAM by siRNA decreased the cell proliferation, migration, invasion and the expression of active form of β-catenin, c-myc and cyclin D1. Our present data suggest that EpICD plays important roles in HCC progression by modulating expression of target genes of EpCAM.

Payandeh M, Shahriari-Ahmadi A, Sadeghi M, Sadeghi E
Correlations between HER2 Expression and Other Prognostic Factors in Breast Cancer: Inverse Relations with the Ki-67 Index and P53 Status.
Asian Pac J Cancer Prev. 2016; 17(3):1015-8 [PubMed] Related Publications
BACKGROUND: Overexpression or amplification of human epidermal growth factor receptor-2 (HER2) is associated with grade of malignancy and a poor prognosis in breast cancer (BC). The aim of this study was to evaluate of value of HER2 as a prognostic marker, and to analyze associations with common histopathological parameters in BC cases.
MATERIALS AND METHODS: Between of 2007 to 2014, 260 patients with BC referred to Oncology Clinic provided cancer tissue samples which underwent immunohistochemistry (IHC) for markers. ER and PR positivity was defined as ≥10% positive tumor cells with nuclear staining. HER2-positive was defined as either HER2 gene amplification by fluorescent in situ hybridization (FISH) or scored as 3+ by IHC. For HER2 (2+), FISH was performed to determine HER2 positivity.
RESULTS: The mean age at diagnosis for the patients with HER2-negative was significantly higher than in HER2-positive cases. Also, there were significant correlations between histological grade, nuclear grade, lymph node metastasis, tumor size, ER status, PR status, p53 overexpression and Ki-67 index with HER2 expression. HER2-negative lesions were of higher grade and more likely to be ER-negative, PR-negative, p53-positive, lymph node metastasis, with a tumor size<2cm and also Ki-67≥20% as compared to the HER2-positive group.
CONCLUSIONS: Contrary to the results of other studies, HER2-positive tumors in our study had a lower Ki-67 index and were p53-positive. Also, Ki-67 proliferation index ≥20% in more studies was associated with p53-positive.Therefore, tumors which are HER2-positive and have a Ki-67≥20% had a more aggressive behavior compared to HER2-positive and Ki-67<20% lesions.

López-Knowles E, Gao Q, Cheang MC, et al.
Heterogeneity in global gene expression profiles between biopsy specimens taken peri-surgically from primary ER-positive breast carcinomas.
Breast Cancer Res. 2016; 18(1):39 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene expression is widely used for the characterisation of breast cancers. Variability due to tissue heterogeneity or measurement error or systematic change due to peri-surgical procedures can affect measurements but is poorly documented. We studied the variability of global gene expression between core-cuts of primary ER+ breast cancers and the impact of delays to tissue stabilisation due to sample X-ray and of diagnostic core cutting.
METHODS: Twenty-six paired core-cuts were taken immediately after tumour excision and up to 90 minutes delay due to sample X-ray; 57 paired core-cuts were taken at diagnosis and 2 weeks later at surgical excision. Whole genome expression analysis was conducted on extracted RNA. Correlations and differences were assessed between the expression of individual genes, gene sets/signatures and intrinsic subtypes.
RESULTS: Twenty-three and 56 sample pairs, respectively, were suitable for analysis. The range of correlations for both sample sets were similar with the majority being >0.97 in both. Correlations between pairs for 18 commonly studied genes were also similar between the studies and mainly with Pearson correlation coefficients >0.6 except for a small number of genes, which had a narrow-dynamic range (e.g. MKI67, SNAI2). There was no systematic difference in intrinsic subtyping between the first and second sample of either set but there was c.15 % discordance between the subtype assignments between the pairs, mainly where the subtyping of individual samples was less certain. Increases in the expression of several stress/early-response genes (e.g. FOS, FOSB, JUN) were found in both studies and confirmed findings in earlier smaller studies. Increased expression of IL6, IGFBP2 and MYC (by 17 %, 14 % and 44 %, respectively) occurred between the samples taken 2 weeks apart and again confirmed findings from an earlier study.
CONCLUSIONS: There is generally good correlation in gene expression between pairs of core-cuts except where genes have a narrow dynamic range. Similar correlation coefficients to the average gene expression profiles of intrinsic subtype, particularly LumA and LumB, can lead to discordances between assigned subtypes. Substantial changes in expression of early-response genes occur within an hour after surgery and in IL6, IGFB2 and MYC as a result of diagnostic core-cut biopsy.
TRIAL REGISTRATION: Trial number CRUK/07/015 . Study start date September 2008.

Abreu MH, Afonso N, Abreu PH, et al.
Male breast cancer: Looking for better prognostic subgroups.
Breast. 2016; 26:18-24 [PubMed] Related Publications
PURPOSE: Male Breast Cancer (MBC) remains a poor understood disease. Prognostic factors are not well established and specific prognostic subgroups are warranted.
PATIENTS/METHODS: Retrospectively revision of 111 cases treated in the same Cancer Center. Blinded-central pathological revision with immunohistochemical (IHQ) analysis for estrogen (ER), progesterone (PR) and androgen (AR) receptors, HER2, ki67 and p53 was done. Cox regression model was used for uni/multivariate survival analysis. Two classifications of Female Breast Cancer (FBC) subgroups (based in ER, PR, HER2, 2000 classification, and in ER, PR, HER2, ki67, 2013 classification) were used to achieve their prognostic value in MBC patients. Hierarchical clustering was performed to define subgroups based on the six-IHQ panel.
RESULTS: According to FBC classifications, the majority of tumors were luminal: A (89.2%; 60.0%) and B (7.2%; 35.8%). Triple negative phenotype was infrequent (2.7%; 3.2%) and HER2 enriched, non-luminal, was rare (≤1% in both). In multivariate analysis the poor prognostic factors were: size >2 cm (HR:1.8; 95%CI:1.0-3.4 years, p = 0.049), absence of ER (HR:4.9; 95%CI:1.7-14.3 years, p = 0.004) and presence of distant metastasis (HR:5.3; 95%CI:2.2-3.1 years, p < 0.001). FBC subtypes were independent prognostic factors (p = 0.009, p = 0.046), but when analyzed only luminal groups, prognosis did not differ regardless the classification used (p > 0.20). Clustering defined different subgroups, that have prognostic value in multivariate analysis (p = 0.005), with better survival in ER/PR+, AR-, HER2-and ki67/p53 low group (median: 11.5 years; 95%CI: 6.2-16.8 years) and worst in PR-group (median:4.5 years; 95%CI: 1.6-7.8 years).
CONCLUSION: FBC subtypes do not give the same prognostic information in MBC even in luminal groups. Two subgroups with distinct prognosis were identified in a common six-IHQ panel. Future studies must achieve their real prognostic value in these patients.

Huszno J, Budryk M, Kołosza Z, et al.
A Comparison between CHEK2*1100delC/I157T Mutation Carrier and Noncarrier Breast Cancer Patients: A Clinicopathological Analysis.
Oncology. 2016; 90(4):193-8 [PubMed] Related Publications
OBJECTIVE: The suppressor gene CHEK2 encodes a cell cycle checkpoint kinase, involved in cell cycle regulation, apoptosis and response to DNA damage. The aim of this study was to analyze the differences between CHEK2 mutation carriers (CHEK2*1100delC/I157T) and noncarriers with respect to clinicopathological factors.
METHODS: We reviewed the medical records of 100 early breast cancer patients (46 mutation carriers and 54 noncarriers) who were treated with chemotherapy, hormonotherapy or trastuzumab.
RESULTS: CHEK2 mutation carriers were older (>65 years) than noncarriers (17 vs. 7%; p = 0.215). Twenty-five (54%) of them had a history of cancer in the family. Gastric cancer in the family history was detected in 11% of mutation carriers and in 2% of noncarriers (p = 0.092). There was a trend for more frequent lymph node metastases in patients without the mutation in comparison to mutation carriers (46 vs. 28%; p = 0.098). Luminal B type breast cancer was detected more often in carriers (39 vs. 20%; p = 0.048). Breast-conserving treatment was also conducted more often in mutation carriers (57 vs. 31%; p = 0.015). Histologic grades G1/G2 were detected more frequently in mutation carriers (82 vs. 70%; p = 0.212).
CONCLUSION: Mutation carriers were characterized by older age, a history of gastric cancer in the family, locally advanced disease, lower histologic grade and luminal B type breast cancer.

Mohammad GH, Olde Damink SW, Malago M, et al.
Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome.
PLoS One. 2016; 11(3):e0151635 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer has a 5-year survival rate of less than 4%. Despite advances in diagnostic technology, pancreatic cancer continues to be diagnosed at a late and incurable stage. Accurate biomarkers for early diagnosis and to predict treatment response are urgently needed. Since alteration of glucose metabolism is one of the hallmarks of cancer cells, we proposed that pyruvate kinase type M2 (M2PK) and lactate dehydrogenase A (LDHA) enzymes could represent novel diagnostic markers and potential therapeutic targets in pancreatic cancer. In 266 tissue sections from normal pancreas, pancreatic cystic neoplasms, pancreatic intraepithelial neoplasia (PanIN) and cancer, we evaluated the expression of PKM2, LDHA, Ki-67 and CD8+ by immunohistochemistry and correlated these markers with clinicopathological characteristics and patient survival. PKM2 and LDHA expression was also assessed by Western blot in 10 human pancreatic cancer cell lines. PKM2 expression increased progressively from cyst through PanIN to cancer, whereas LDHA was overexpressed throughout the carcinogenic process. All but one cell line showed high expression of both proteins. Patients with strong PKM2 and LDHA expression had significantly worse survival than those with weak PKM2 and/or LDHA expression (7.0 months vs. 27.9 months, respectively, p = 0.003, log rank test). The expression of both PKM2 and LDHA correlated directly with Ki-67 expression, and inversely with intratumoral CD8+ cell count. PKM2 was significantly overexpressed in poorly differentiated tumours and both PKM2 and LDHA were overexpressed in larger tumours. Multivariable analysis showed that combined expression of PKM2 and LDHA was an independent poor prognostic marker for survival. In conclusion, our results demonstrate a high expression pattern of two major glycolytic enzymes during pancreatic carcinogenesis, with increased expression in aggressive tumours and a significant adverse effect on survival.

Buhrmann C, Shayan P, Popper B, et al.
Sirt1 Is Required for Resveratrol-Mediated Chemopreventive Effects in Colorectal Cancer Cells.
Nutrients. 2016; 8(3):145 [PubMed] Free Access to Full Article Related Publications
Sirt1 is a NAD⁺-dependent protein-modifying enzyme involved in regulating gene expression, DNA damage repair, metabolism and survival, as well as acts as an important subcellular target of resveratrol. The complex mechanisms underlying Sirt1 signaling during carcinogenesis remain controversial, as it can serve both as a tumor promoter and suppressor. Whether resveratrol-mediated chemopreventive effects are mediated via Sirt1 in CRC growth and metastasis remains unclear; which was the subject of this study. We found that resveratrol suppressed proliferation and invasion of two different human CRC cells in a dose-dependent manner, and interestingly, this was accompanied with a significant decrease in Ki-67 expression. By transient transfection of CRC cells with Sirt1-ASO, we demonstrated that the anti-tumor effects of resveratrol on cells was abolished, suggesting the essential role of this enzyme in the resveratrol signaling pathway. Moreover, resveratrol downregulated nuclear localization of NF-κB, NF-κB phosphorylation and its acetylation, causing attenuation of NF-κB-regulated gene products (MMP-9, CXCR4) involved in tumor-invasion and metastasis. Finally, Sirt1 was found to interact directly with NF-κB, and resveratrol did not suppress Sirt1-ASO-induced NF-κB phosphorylation, acetylation and NF-κB-regulated gene products. Overall, our results demonstrate that resveratrol can suppress tumorigenesis, at least in part by targeting Sirt1 and suppression of NF-κB activation.

Aziz S, Wik E, Knutsvik G, et al.
Evaluation of Tumor Cell Proliferation by Ki-67 Expression and Mitotic Count in Lymph Node Metastases from Breast Cancer.
PLoS One. 2016; 11(3):e0150979 [PubMed] Free Access to Full Article Related Publications
Few studies have addressed the risk of recurrence by assessing proliferation markers in lymph node metastasis from breast cancer. Here, we aimed to examine Ki-67 expression and mitotic count in lymph nodes in comparison with primary tumors. A cohort of node positive breast cancer (n = 168) was studied as a part of the prospective Norwegian Breast Cancer Screening Program (1996-2009). The percentage of Ki-67 positivity was counted per 500 tumor cells in hot-spot areas (x630). Mitotic count was conducted in the most cellular and mitotic active areas in 10 high power fields (x400). Our results showed that Ki-67 and mitotic count were significantly correlated between primary tumor and lymph nodes (Spearman`s correlation 0. 56 and 0.46, respectively) and were associated with most of the histologic features of the primary tumor. Univariate survival analysis (log-rank test) showed that high Ki-67 and mitotic count in the primary tumor and lymph node metastasis significantly predicted risk of recurrence. In multivariate analysis, mitotic count in the lymph node metastasis was an independent predictor of tumor recurrence. In conclusion, proliferation markers in lymph node metastases significantly predicted disease free survival in node positive breast cancer.

Ormenisan C, Kubik M, Legrand S, et al.
The potential of ki67 and p53 assessment in development of individualized targeted therapy in breast cancer patients.
Pathologica. 2015 Sep-Dec; 107(3-4):177-80 [PubMed] Related Publications
INTRODUCTION: Despite the improvement of diagnostic methods and chemotherapeutic regimens in breast cancer, overall 5-year survival significantly depends on the stage of the disease. Over expression of tumor suppressor gene p53 and the marker for cellular proliferation Ki67 in breast cancer may have prognostic significance.
METHODS: We evaluated 675 patients diagnosed with breast cancer at UF Health Jacksonville between January 2000 and June 2007 with up to 5-year follow up. The aim of the study was to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 may predict outcome, the 'hazard' of dying. Cox's proportional hazards models were used to control for age (< 50 vs. ≥ 50), race (white vs. other), lymph node group (negative vs. positive), ER (estrogen receptor) group (negative vs. positive), PR (progesterone receptor) group (negative vs. positive), and tumor type.
RESULTS: When only p53 was considered in the model, the hazard of dying was significantly higher for p53 positive compared to p53 negative (HR = 1.32, 95% CI 1.02, 1.70, p = 0.036). When only ki67 was considered in the model, the hazard of dying was significantly higher for ki67 positive compared to ki67 negative (Hazard ratio = 1.64, 95% CI 1.08, 2.49, p = 0.021). Neither of the two markers, nor their interaction was significant when all variables were considered in the model.
DISCUSSION: This study confirms the expression of p53 and Ki67 as strong individual indicators of patient outcome. However, when controlling for the other variables, the two markers are not independent predictors. Future studies that will include these markers might help design targeted therapy.

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