Publications by authors named "Karin Collett"

15 Publications

  • Page 1 of 1

Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies.

Front Immunol 2020 8;11:564712. Epub 2020 Oct 8.

Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

Preeclampsia is a hypertensive and inflammatory pregnancy disorder associated with cholesterol accumulation and inflammation at the maternal-fetal interface. Preeclampsia can be complicated with fetal growth restriction (FGR) and shares risk factors and pathophysiological mechanisms with cardiovascular disease. Cholesterol crystal mediated NLRP3 inflammasome activation is central to cardiovascular disease and the pathway has been implicated in placental inflammation in preeclampsia. Direct maternal-fetal interaction occurs both in the uterine wall decidua and at the placental surface and these aligned sites constitute the maternal-fetal interface. This study aimed to investigate cholesterol crystal accumulation and NLRP3 inflammasome expression by maternal and fetal cells in the uterine wall decidua of normal and preeclamptic pregnancies. Pregnant women with normal ( = 43) and preeclamptic pregnancies with ( = 28) and without ( = 19) FGR were included at delivery. Cholesterol crystals were imaged in decidual tissue by both second harmonic generation microscopy and polarization filter reflected light microscopy. Quantitative expression analysis of NLRP3, IL-1β and cell markers was performed by immunohistochemistry and automated image processing. Functional NLRP3 activation was assessed in cultured decidual explants. Cholesterol crystals were identified in decidual tissue, both in the tissue stroma and near uterine vessels. The cholesterol crystals in decidua varied between pregnancies in distribution and cluster size. Decidual expression of the inflammasome components NLRP3 and IL-1β was located to fetal trophoblasts and maternal leukocytes and was strongest in areas of proximity between these cell types. Pathway functionality was confirmed by cholesterol crystal activation of IL-1β in cultured decidual explants. Preeclampsia without FGR was associated with increased trophoblast dependent NLRP3 and IL-1β expression, particularly in the decidual areas of trophoblast and leukocyte proximity. Our findings suggest that decidual accumulation of cholesterol crystals may activate the NLRP3 inflammasome and contribute to decidual inflammation and that this pathway is strengthened in areas with close maternal-fetal interaction in preeclampsia without FGR.
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http://dx.doi.org/10.3389/fimmu.2020.564712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578244PMC
May 2021

Stathmin expression associates with vascular and immune responses in aggressive breast cancer subgroups.

Sci Rep 2020 02 19;10(1):2914. Epub 2020 Feb 19.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, N-5021, Norway.

Studies indicate that stathmin expression associates with PI3K activation in breast cancer, suggesting stathmin as a marker for targetable patient subgroups. Here we assessed stathmin in relation to tumour proliferation, vascular and immune responses, BRCA1 germline status, basal-like differentiation, clinico-pathologic features, and survival. Immunohistochemical staining was performed on breast cancers from two series (cohort 1, n = 187; cohort 2, n = 198), and mass spectrometry data from 24 cases and 12 breast cancer cell lines was examined for proteomic profiles. Open databases were also explored (TCGA, METABRIC, Oslo2 Landscape cohort, Cancer Cell Line Encyclopedia). High stathmin expression associated with tumour proliferation, p53 status, basal-like differentiation, BRCA1 genotype, and high-grade histology. These patterns were confirmed using mRNA data. Stathmin mRNA further associated with tumour angiogenesis, immune responses and reduced survival. By logistic regression, stathmin protein independently predicted a BRCA1 genotype (OR 10.0, p = 0.015) among ER negative tumours. Cell line analysis (Connectivity Map) implied PI3K inhibition in tumours with high stathmin. Altogether, our findings indicate that stathmin might be involved in the regulation of tumour angiogenesis and immune responses in breast cancer, in addition to tumour proliferation. Cell data point to potential effects of PI3K inhibition in tumours with high stathmin expression.
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http://dx.doi.org/10.1038/s41598-020-59728-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031232PMC
February 2020

Placental inflammation by HMGB1 activation of TLR4 at the syncytium.

Placenta 2018 12 2;72-73:53-61. Epub 2018 Nov 2.

Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), NO-7491, Trondheim, Norway. Electronic address:

Introduction: Normal pregnancy is characterized by an elevated inflammatory state involving the placenta. The placental inflammation is further increased in preeclampsia, resulting in release of harmful danger signals to the maternal circulation. Activation of toll-like receptors (TLR)2 and TLR4 by endogenous danger signals plays a role in inflammatory diseases. Placental TLR2 and TLR4 expression has been reported, and high mobility group box 1 (HMGB1) is a likely endogenous activator of these receptors. We aimed to examine HMGB1 activation of TLR2 and TLR4 as mechanisms of placental inflammation in normal and preeclamptic pregnancies, by combined analysis of expression and function of the ligand HMGB1, the receptors TLR2 and TLR4, and the cytokine responder interleukin (IL)-8.

Methods: Protein expression was analyzed in placental tissue from normal and preeclamptic pregnancies, and cytokine responses to two distinct HMGB1 isoforms were examined in placental explants and trophoblasts. Inflammatory and anti-angiogenic markers were measured in maternal serum.

Results: We demonstrated strong co-localized expression of HMGB1, TLR4 and IL-8 in the syncytium layer of the placenta. Syncytium TLR4 expression and maternal serum levels of IL-8 were significantly increased in preeclamptic compared to normal pregnancies. Functionality was confirmed by TLR4-dependent release of IL-8 from placental explants and trophoblasts in response to the inflammatory isoform of HMGB1.

Discussion: This demonstrates a role for the HMGB1-TLR4 pathway at the syncytium layer and suggests involvement in placental inflammation and preeclampsia.
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http://dx.doi.org/10.1016/j.placenta.2018.10.011DOI Listing
December 2018

Placenta, cord and membranes: a dual center validation study of midwives' classifications and notifications to the Medical Birth Registry of Norway.

Acta Obstet Gynecol Scand 2017 Sep 8;96(9):1120-1127. Epub 2017 Jun 8.

Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.

Introduction: A validation of data regarding the placenta, cord and membranes in Medical Birth Registry of Norway (MBRN) is lacking. Here we investigate the inter- and intra-observer agreement of observations regarding the placenta, cord and membranes to the MBRN in two institutions.

Material And Methods: We conducted a dual center validation study of data regarding placenta, cord and membranes. In the inter-observer study, 196 placentas in two institutions were examined by the attending midwife and a blinded colleague, whereas in the intra-observer study registrations by the attending midwife on 195 placentas were compared with her own registrations to the MBRN. In a separate sample consisting of 51 placental pathology reports, midwives' registrations to the MBRN were compared with the pathology report. For categorical and continuous variables, agreement was assessed by kappa value and paired sample t-test, respectively.

Results: Inter-observer agreement between two midwives for cord insertion site and bi-placenta, cord knots and vessel anomalies were good (kappa values >0.79 and >0.96, respectively). The inter- and intra-observer study showed no significant differences regarding placental weight and cord length (p = 0.31 and 0.28, p = 0.71 and 0.39, respectively). The inter-observer agreement between the pathology reports and midwives' registrations was good for gross placental and cord variants (kappa 0.73-1.0), but there were significant differences in placental weight and cord length (p < 0.0001).

Conclusions: The results suggest that the validity of data regarding placenta and cord in the MBRN is sufficiently high to justify future large-scale epidemiologic research based on this database.
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http://dx.doi.org/10.1111/aogs.13164DOI Listing
September 2017

Tumour cell invasion into blood vessels is significantly related to breast cancer subtypes and decreased survival.

J Clin Pathol 2017 Apr 9;70(4):313-319. Epub 2016 Sep 9.

Department of Clinical Medicine, Section for Pathology and Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway.

Aims: Vascular invasion in breast cancer is associated with increased risk of recurrence, metastases and death from disease. However, there are few studies discriminating between blood vessel invasion (BVI) and lymphatic vessel involvement (LVI).

Methods: A population-based series of 282 breast cancers was examined (200 screen-detected and 82 interval patients) with respect to BVI and LVI in addition to basic features and molecular subtypes, using CD31 and D2-40 antibodies. This series is part of the prospective Norwegian Breast Cancer Screening Program.

Results: The frequency of LVI and BVI was 25% and 15%, respectively. BVI was associated with HER2-positive and basal-like tumours, and several features of aggressive breast cancer, whereas LVI showed weaker associations. BVI was the strongest factor to predict interval cancer presentation. BVI showed significant associations with recurrence-free survival and disease-specific survival in univariate and multivariate analyses, whereas LVI was not significant.

Conclusions: Our findings indicate that BVI by tumour cells is strongly associated with aggressive tumour features including a basal-like phenotype, and BVI was an independent prognostic factor in contrast to what was found for LVI.
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http://dx.doi.org/10.1136/jclinpath-2016-203861DOI Listing
April 2017

QSOX1 expression is associated with aggressive tumor features and reduced survival in breast carcinomas.

Mod Pathol 2016 12 26;29(12):1485-1491. Epub 2016 Aug 26.

Centre for Cancer Biomarkers, CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.

The biological role of quiescin sulfhydryl oxidase 1 (QSOX1) in tumor development is not well known, and its relation to breast cancer progression and prognosis is controversial. Here, our aim was to study the expression pattern and prognostic impact of QSOX1 in breast cancer, in relation to molecular subgroups and tumor cell proliferation. We examined a population-based series as part of the prospective Norwegian Breast Cancer Screening Program, including all women (50-69 years) diagnosed with breast cancer in one county of Norway during 1996-2003. QSOX1 expression was assessed by immunohistochemistry on tissue microarrays (n=458). Median follow-up time was 13 years. High expression of QSOX1 protein was associated with features of poor prognosis including high histologic grade, hormone receptor negativity, HER2 positivity, and increased tumor cell proliferation. High QSOX1 expression was further associated with reduced breast cancer-specific survival in both univariate and multivariate analysis, independent of molecular subtypes. High QSOX1 expression is a strong and independent factor of reduced survival in breast cancer, also reflected by elevated levels in more aggressive molecular subgroups. QSOX1 expression may represent a biomarker for aggressive disease and a potential treatment target.
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http://dx.doi.org/10.1038/modpathol.2016.148DOI Listing
December 2016

Evaluation of Ki67 expression across distinct categories of breast cancer specimens: a population-based study of matched surgical specimens, core needle biopsies and tissue microarrays.

PLoS One 2014 6;9(11):e112121. Epub 2014 Nov 6.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway.

Introduction: Tumor cell proliferation in breast cancer is strongly prognostic and may also predict response to chemotherapy. However, there is no consensus on counting areas or cut-off values for patient stratification. Our aim was to assess the matched level of proliferation by Ki67 when using different tissue categories (whole sections, WS; core needle biopsies, CNB; tissue microarrays, TMA), and the corresponding prognostic value.

Methods: We examined a retrospective, population-based series of breast cancer (n = 534) from the Norwegian Breast Cancer Screening Program. The percentage of Ki67 positive nuclei was evaluated by visual counting on WS (n = 534), CNB (n = 154) and TMA (n = 459).

Results: The median percentage of Ki67 expression was 18% on WS (hot-spot areas), 13% on CNB, and 7% on TMA, and this difference was statistically significant in paired cases. Increased Ki67 expression by all evaluation methods was associated with aggressive tumor features (large tumor diameter, high histologic grade, ER negativity) and reduced patient survival.

Conclusion: There is a significant difference in tumor cell proliferation by Ki67 across different sample categories. Ki67 is prognostic over a wide range of cut-off points and for different sample types, although Ki67 results derived from TMA sections are lower compared with those obtained using specimens from a clinical setting. Our findings indicate that specimen specific cut-off values should be applied for practical use.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112121PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223011PMC
April 2016

Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer.

Proc Natl Acad Sci U S A 2012 May 15;109(22):8699-704. Epub 2012 May 15.

Vascular Biology Program, Children's Hospital Boston, Boston, MA 02115, USA.

The mechanisms underlying tumor dormancy have been elusive and not well characterized. We recently published an experimental model for the study of human tumor dormancy and the role of angiogenesis, and reported that the angiogenic switch was preceded by a local increase in VEGF-A and basic fibroblast growth factor. In this breast cancer xenograft model (MDA-MB-436 cells), analysis of differentially expressed genes revealed that heat shock protein 27 (HSP27) was significantly up-regulated in angiogenic cells compared with nonangiogenic cells. The effect of HSP27 down-regulation was further evaluated in cell lines, mouse models, and clinical datasets of human patients with breast cancer and melanoma. Stable down-regulation of HSP27 in angiogenic tumor cells was followed by long-term tumor dormancy in vivo. Strikingly, only 4 of 30 HSP27 knockdown xenograft tumors initiated rapid growth after day 70, in correlation with a regain of HSP27 protein expression. Significantly, no tumors escaped from dormancy without HSP27 expression. Down-regulation of HSP27 was associated with reduced endothelial cell proliferation and decreased secretion of VEGF-A, VEGF-C, and basic fibroblast growth factor. Conversely, overexpression of HSP27 in nonangiogenic cells resulted in expansive tumor growth in vivo. By clinical validation, strong HSP27 protein expression was associated with markers of aggressive tumors and decreased survival in patients with breast cancer and melanoma. An HSP27-associated gene expression signature was related to molecular subgroups and survival in breast cancer. Our findings suggest a role for HSP27 in the balance between tumor dormancy and tumor progression, mediated by tumor-vascular interactions. Targeting HSP27 might offer a useful strategy in cancer treatment.
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http://dx.doi.org/10.1073/pnas.1017909109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365195PMC
May 2012

Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival.

Proc Natl Acad Sci U S A 2010 Jan 28;107(3):1124-9. Epub 2009 Dec 28.

Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway.

Metastasis underlies the majority of cancer-related deaths. Thus, furthering our understanding of the molecular mechanisms that enable tumor cell dissemination is a vital health issue. Epithelial-to-mesenchymal transitions (EMTs) endow carcinoma cells with enhanced migratory and survival attributes that facilitate malignant progression. Characterization of EMT effectors is likely to yield new insights into metastasis and novel avenues for treatment. We show that the presence of the receptor tyrosine kinase Axl in primary breast cancers independently predicts strongly reduced overall patient survival, and that matched patient metastatic lesions show enhanced Axl expression. We demonstrate that Axl is strongly induced by EMT in immortalized mammary epithelial cells that establishes an autocrine signaling loop with its ligand, Gas6. Epiallelic RNA interference analysis in metastatic breast cancer cells delineated a distinct threshold of Axl expression for mesenchymal-like in vitro cell invasiveness and formation of tumors in foreign and tissue-engineered microenvironments in vivo. Importantly, in two different optical imaging-based experimental breast cancer models, Axl knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and several major organs and increased overall survival. These findings suggest that Axl represents a downstream effector of the tumor cell EMT that is required for breast cancer metastasis. Thus, the detection and targeted treatment of Axl-expressing tumors represents an important new therapeutic strategy for breast cancer.
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http://dx.doi.org/10.1073/pnas.0909333107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824310PMC
January 2010

Estrogen receptor beta--an independent prognostic marker in estrogen receptor alpha and progesterone receptor-positive breast cancer?

APMIS 2009 Sep;117(9):644-50

Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital, Bergen, Norway.

Both subtypes of estrogen receptor (ER), ERalpha and ERbeta, are normally present in the mammary gland. The role of ERalpha as a prognostic marker in breast cancer is well established due to the beneficial effect of providing tamoxifen as adjuvant therapy. The role of ERbeta, however, is less clear. To gain insight into the importance of ERbeta in breast cancer, 145 primary breast cancers were examined by immunohistochemistry for ERbeta, and the expression level was compared with ERalpha and progesterone receptor (PR) status. Especially, we wanted to examine the significance of ERbeta in the contrasting ERalpha+/PR+ and ERalpha-/PR- subgroups. In the ERalpha+/PR+ subgroup (dual positive), the survival difference between patients with low, medium and high ER beta level was statistically significant (p = 0.004), with more than 70% of patients with medium and high ERbeta levels surviving 100 months, compared with less than 30% in the group with low ERbeta level. Further, for ERalpha+/PR+ patients there was a reduced risk of fatal outcome by multivariate analysis with increasing ERbeta levels (p(trend) < 0.01 [univariate analysis]; p(trend) = 0.05 [multivariate analysis]). The risk was 31% and 27% for medium and high ERbeta levels, respectively, compared with low ERbeta level, adjusting for standard prognostic factors such as tumor diameter, nuclear tumor grade (quantified by mean nuclear area), lymph node status, and patient age at operation. For patients with ERalpha-/PR- tumors (dual negative), however, there was no association between ERbeta levels and patient outcome. Our findings indicate that ERbeta expression provides independent prognostic information for breast cancers with ERalpha/PR-positive status, a feature typical among screen-detected breast cancers. The role of ERbeta needs to be further evaluated especially in this group of breast cancers.
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http://dx.doi.org/10.1111/j.1600-0463.2009.02510.xDOI Listing
September 2009

Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer.

Clin Cancer Res 2006 Feb;12(4):1168-74

Section for Pathology, The Gade Institute, Haukeland University Hospital, Norway.

The polycomb group protein enhancer of zeste homologue 2 (EZH2) has been linked to invasive properties of aggressive breast cancer. In this report, tissue microarray analysis of 190 breast carcinomas from a nested case-control study shows that EZH2 is significantly associated with interval breast cancers. Further, a strong relationship was found with tumor cell proliferation (by Ki-67 expression), locally advanced disease, metastasis at presentation, markers of the basal epithelial phenotype (positivity for cytokeratin 5/6 or P-cadherin), and p53 status. EZH2 expression was also significantly associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype. For prediction of aggressive disease (any event of locally advanced disease, lymph node spread, or distant spread), EZH2 was the only variable of significance in multivariate analysis, whereas no additional information was given by Ki-67. Although EZH2 expression was significant in univariate survival analysis, only tumor cell proliferation and lymph node status were significant in the final multivariate model. In conclusion, our findings indicate an important relationship not only between EZH2 and markers of tumor cell proliferation but also with aggressive disease. These findings might be practically important and relevant because the polycomb group proteins have recently been suggested as candidates for targeted therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-05-1533DOI Listing
February 2006

EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast.

J Clin Oncol 2006 Jan 5;24(2):268-73. Epub 2005 Dec 5.

Gade Institute, Section of Pathology, Bergen, Norway.

Purpose: EZH2 is a member of the polycomb group of genes and important in cell cycle regulation. Increased expression of EZH2 has been associated previously with invasive growth and aggressive clinical behavior in prostate and breast cancer, but the relationship with tumor cell proliferation has not been examined in human tumors. The purpose of this study was to validate previous findings in a population-based setting, also including tumors that have not been studied previously.

Patients And Methods: In our study of nearly 700 patients, we examined EZH2 expression and its association with tumor cell proliferation and other tumor markers, clinical features, and prognosis in cutaneous melanoma and cancers of the endometrium, prostate, and breast.

Results: Strong EZH2 expression was associated with increased tumor cell proliferation in all four cancer types. Associations were also found between EZH2 and important clinicopathologic variables. EZH2 expression showed significant prognostic impact in melanoma, prostate, and endometrial carcinoma in univariate survival analyses, and revealed independent prognostic importance in carcinoma of the endometrium and prostate. CONCLUSION Our findings point at EZH2 as a novel and independent prognostic marker in endometrial cancer, and validate previous findings on prostate and breast cancer. Further, EZH2 expression was associated with features of aggressive cutaneous melanoma. The fact that EZH2 might identify increased tumor cell proliferation and aggressive subgroups in several cancers may be of practical interest because the polycomb group proteins have been suggested as candidates for targeted therapy. EZH2 expression should, therefore, be further examined as a possible predictive factor.
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http://dx.doi.org/10.1200/JCO.2005.01.5180DOI Listing
January 2006

A basal epithelial phenotype is more frequent in interval breast cancers compared with screen detected tumors.

Cancer Epidemiol Biomarkers Prev 2005 May;14(5):1108-12

Vascular Biology Program, Karp Family Research Labs 12.125, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115-5737, USA.

Interval breast cancer reduce the effectiveness of mammography screening programs. We studied 95 interval cancers, diagnosed during 1996 to 2001 as part of the population-based Norwegian Breast Cancer Screening Program. These cases were matched on size (+/-2.0 mm) to 95 screen-detected breast cancers, and the tumors were compared by immunohistochemical methods using tissue microarrays. Patients with interval cancers were more likely to be younger [odds ratio (OR), 4.7; P = 0.0001], to have dense breasts (OR, 3.4; P = 0.004), and to have estrogen receptor-negative tumors (OR, 2.6, P = 0.01), and p53 expression was more frequent (OR, 4.0; P = 0.001). Notably, interval cancers were more likely to have a basal epithelial phenotype, in that expression of cytokeratin 5/6 (OR, 2.3; P = 0.04) and P-cadherin (OR, 2.5; P = 0.04) was more frequent in interval cases than in size-matched, screen-detected tumors. In a logistic regression model, p53 expression, age, and breast density were independent predictors of interval cancers. Our data suggest that breast cancers with a basal epithelial phenotype are more likely than nonbasal breast cancers to present between regular mammograms.
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http://dx.doi.org/10.1158/1055-9965.EPI-04-0394DOI Listing
May 2005
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