| 1. |
- Lu, Yingchang, et al.
(författare)
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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.
- 2018
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 78:18, s. 5419-5430
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Tidskriftsartikel (refereegranskat)abstract
- .AbstractLarge-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
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| 2. |
- Abrahamsson, Annelie, et al.
(författare)
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Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo
- 2016
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Ingår i: Oncoimmunology. - : TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 5:10
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is one of the hallmarks of carcinogenesis. High mammographic density has been associated with increased risk of breast cancer but the mechanisms behind are poorly understood. We evaluated whether breasts with different mammographic densities exhibited differences in the inflammatory microenvironment.Postmenopausal women attending the mammography-screening program were assessed having extreme dense, n = 20, or entirely fatty breasts (nondense), n = 19, on their regular mammograms. Thereafter, the women were invited for magnetic resonance imaging (MRI), microdialysis for the collection of extracellular molecules in situ and a core tissue biopsy for research purposes. On the MRI, lean tissue fraction (LTF) was calculated for a continuous measurement of breast density. LTF confirmed the selection from the mammograms and gave a continuous measurement of breast density. Microdialysis revealed significantly increased extracellular in vivo levels of IL-6, IL-8, vascular endothelial growth factor, and CCL5 in dense breast tissue as compared with nondense breasts. Moreover, the ratio IL-1Ra/IL-1 was decreased in dense breasts. No differences were found in levels of IL-1, IL-1Ra, CCL2, leptin, adiponectin, or leptin:adiponectin ratio between the two breast tissue types. Significant positive correlations between LTF and the pro-inflammatory cytokines as well as between the cytokines were detected. Stainings of the core biopsies exhibited increased levels of immune cells in dense breast tissue.Our data show that dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment and, if confirmed in a larger cohort, suggests novel targets for prevention therapies for women with dense breast tissue.
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| 3. |
- Abrahamsson, Annelie, et al.
(författare)
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Downregulation of tumor suppressive microRNAs in vivo in dense breast tissue of postmenopausal women
- 2017
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Ingår i: Oncotarget. - : Impact Journals LCC. - 1949-2553. ; 8:54, s. 92134-92142
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Tidskriftsartikel (refereegranskat)abstract
- Women with dense breast tissue on mammography are at higher risk of developing breast cancer but the underlying mechanisms are not well understood. De-regulation of microRNAs (miRNAs) has been associated with the onset of breast cancer. miRNAs in the extracellular space participate in the regulation of the local tissue microenvironment. Here, we recruited 39 healthy postmenopausal women attending their mammography-screen that were assessed having extreme dense or entirely fatty breasts (nondense). Microdialysis was performed in breast tissue and a reference catheter was inserted in abdominal subcutaneous fat for local sampling of extracellular compounds. Three miRNAs, associated with tumor suppression, miR-193b, miR-365a, and miR-452 were significantly down-regulated in dense breast tissue compared with nondense breast tissue. In addition, miR-452 exhibited significant negative correlations with several pro-inflammatory cytokines in vivo, which was confirmed in vitro by overexpression of miR-452 in breast cancer cells. No differences were found of miR-21, -29a, -30c, 146a, -148a, -203, or -451 in breast tissue and no miRs were different in plasma. Extracellular miRNAs may be among factors that should be included in studies of novel prevention strategies for breast cancer.
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| 4. |
- Abrahamsson, Annelie, et al.
(författare)
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Equal Pro-inflammatory Profiles of CCLs, CXCLs, and Matrix Metalloproteinases in the Extracellular Microenvironment In Vivo in Human Dense Breast Tissue and Breast Cancer
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The inflammatory microenvironment affects breast cancer progression. Proteins that govern the inflammatory response are secreted into the extracellular space, but this compartment still needs to be characterized in human breast tissues in vivo. Dense breast tissue is a major risk factor for breast cancer by yet unknown mechanisms and no non-toxic prevention for these patients exists. Here, we used the minimal invasive technique of microdialysis for sampling of extracellular proteins in live tissues in situ in breast cancers of women before surgery and in healthy women having dense or non-dense breast tissue on mammography. Proteins were profiled using a proximity extension assay. Out of the 32 proteins assessed, 26 exhibited similar profiles in breast cancers and dense breast tissues; CCL-4, -7, -8, -11, -15, -16, -22, -23, and -25, CXCL-5, -8, -9, -16 as well as sIL-6R, IL-18, vascular endothelial growth factor, TGF-a, fibroblast growth factor 19, matrix metalloproteinase (MMP)-1, -2, -3, and urokinase-type plasminogen activator were all increased, whereas CCL-3, CX3CL1, hepatocyte growth factor, and MMP-9 were unaltered in the two tissues. CCL-19 and -24, CXCL-1 and -10, and IL-6 were increased in dense breast tissue only, whereas IL-18BP was increased in breast cancer only. Our results provide novel insights in the inflammatory microenvironment in human breast cancer in situ and define potential novel therapeutic targets. Additionally, we show previously unrecognized similarities of the pro-inflammatory microenvironment in dense breast tissue and breast cancer in vivo suggesting that anti-inflammatory breast cancer prevention trials for women with dense breast tissue may be feasible.
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| 5. |
- Abrahamsson, Annelie, 1966-, et al.
(författare)
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Increased nutrient availability in dense breast tissue of postmenopausal women in vivo
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic reprogramming is a hallmark of cancer. Nutrient availability in the tissue microenvironment determines cellular events and may play a role in breast carcinogenesis. High mammographic density is an independent risk factor for breast cancer. Whether nutrient availability differs in normal breast tissues with various densities is unknown. Therefore we investigated whether breast tissues with various densities exhibited differences in nutrient availability. Healthy postmenopausal women from the regular mammographic screening program who had either predominantly fatty breast tissue (nondense), n = 18, or extremely dense breast tissue (dense), n = 20, were included. Microdialysis was performed for the in vivo sampling of amino acids (AAs), analyzed by ultra-high performance liquid chromatography with tandem mass spectroscopy, glucose, lactate and vascular endothelial growth factor (VEGF) in breast tissues and, as a control, in abdominal subcutaneous (s.c.) fat. We found that dense breast tissue exhibited significantly increased levels of 20 proteinogenic AAs and that 18 of these AAs correlated significantly with VEGF. No differences were found in the s.c. fat, except for one AA, suggesting tissue-specific alterations in the breast. Glucose and lactate were unaltered. Our findings provide novel insights into the biology of dense breast tissue that may be explored for breast cancer prevention strategies.
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| 6. |
- Lindahl, Gabriel, et al.
(författare)
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Increased Extracellular Osteopontin Levels in Normal Human Breast Tissue at High Risk of Developing Cancer and Its Association With Inflammatory Biomarkers in situ
- 2019
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Ingår i: Frontiers in Oncology. - : FRONTIERS MEDIA SA. - 2234-943X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Mammographic breast density is a strong independent risk factor for breast cancer (BC), but the molecular mechanisms behind this risk is yet undetermined and prevention strategies for these women are lacking. The anti-estrogen tamoxifen may reduce the risk of BC but this treatment is associated with severe side effects. Thus, other means for BC prevention, such as diet interventions, need to be developed. Osteopontin (OPN) is a major mediator of inflammation which is key in carcinogenesis. OPN may be cleaved by proteases in the tissue and cleaved OPN may in turn induce an inflammatory cascade in the extracellular microenvironment. We aimed to determine if extracellular OPN was altered in BC and in normal breast tissue with different densities and if tamoxifen or a diet of flaxseed could modify OPN levels. The study comprised 103 women; 13 diagnosed with BC, 42 healthy post-menopausal women with different breast densities at their mammography screen, and 34 post-menopausal women who added 25 g of ground flaxseed/day or were treated with tamoxifen 20 mg/day and were investigated before and after 6 weeks of exposure. Additionally, 10 premenopausal women who added flaxseed for one menstrual cycle and four who were investigated in two unexposed consecutive luteal phases of the menstrual cycle. Microdialysis was used to sample extracellular proteins in vivo in breast tissue and proteins were quantified using a multiplex proximity extension assay. We found that, similar to BC, extracellular in vivo OPN levels were significantly increased in dense breast tissue. Additionally, significant correlations were found between OPN and chemokine (C-X-C motif) ligand (CXCL)-1, -8, -9, -10, and - 11, interleukin-6, vascular endothelial growth factor, matrix metalloproteinase (MMP)-1, - 2, -3, 7, and -12 and urokinase-type plasminogen activator whereas no correlations were found with MMP-9, chemokine (C-C motif) ligand (CCL)-2, and -5. Estradiol did not affect OPN levels in breast tissue. None of the interventions altered OPN levels. The pro-tumorigenic protein OPN may indeed be a molecular target for BC prevention in women with increased breast density but other means than tamoxifen or flaxseed i.e., more potent anti-inflammatory approaches, need to be evaluated for this purpose.
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| 7. |
- Lundberg, Peter, 1958-, et al.
(författare)
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Breast density is strongly associated with multiparametric magnetic resonance imaging biomarkers and pro-tumorigenic proteins in situ
- 2022
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Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 127, s. 2025-2033
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Tidskriftsartikel (refereegranskat)abstract
- Background High mammographic density is an independent risk factor for breast cancer by poorly understood molecular mechanisms. Women with dense breasts often undergo conventional magnetic resonance imaging (MRI) despite its limited specificity, which may be increased by diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) and contrast. How these modalities are affected by breast density per se and their association with the local microenvironment are undetermined. Methods Healthy postmenopausal women attending mammography screen with extremely dense or entirely fatty breasts underwent multiparametric MRI for analyses of lean tissue fraction (LTF), ADC and perfusion dynamics. Microdialysis was used for extracellular proteomics in situ. Results Significantly increased LTF and ADC and delayed perfusion were detected in dense breasts. In total, 270 proteins were quantified, whereof 124 related to inflammation, angiogenesis, and cellular growth were significantly upregulated in dense breasts. Most of these correlated significantly with LTF, ADC and the perfusion data. Conclusions ADC and perfusion characteristics depend on breast density, which should be considered during the implementation of thresholds for malignant lesions. Dense and nondense breasts are two essentially different biological entities, with a pro-tumorigenic microenvironment in dense breasts. Our data reveal several novel pathways that may be explored for breast cancer prevention strategies.
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| 8. |
- Spångeus, Anna, 1975-, et al.
(författare)
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DENUSOMAB PERSISTENCE DURING THE COVID PANDEMIC (Poster 883)
- 2021
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To investigate the effect of the COVID-19 pandemic on denosumab persistence. Methods: All patients who initiated denosumab treatment at our outpatient care (osteoporosis/endocrinology unit) between 2016-2019 were included and date of injections were recorded from case records. Persistence was analyzed regarding 2-y persistence and 1-y persistence. Persistence was defined as a maximum interval of either 1) 8 months (m) [6+2m], or 2) 9m [6+3m]. Results: In total 171 patients were included. Mean age was 74.3+10.2 y (range 35-93 y) and 87% were women. Age and gender distribution did not differ significantly between the year of denosumab initiation. The 2-y persistence rate (8-m interval permitted) was lower in patients starting denosumab 2019 than those starting 2016-1018, i.e., 69% vs. 83%, p=0.044. No significant difference was seen analyzing 1-y persistence in the same groups (87 vs. 91%, p=0.410). When using a more liberal persistence definition, i.e., 9+m interval permitted, no difference was seen between 2 y persistence, 77 vs. 83%, p=0.341. Conclusion: The present study indicates that a higher number of patients got their injection later than recommended during the pandemic, but despite high pressure on our healthcare system and health concerns in the general population, no significant influence on denosumab persistence using a more liberal interval allowance was seen in this outpatient osteoporosis group.
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