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Fredholm, H., Magnusson, K., Lindstrom, L. S., Tobin, N. P., Lindman, H., Bergh, J., . . . Fredriksson, I. (2017). Breast cancer in young women and prognosis: How important are proliferation markers?. European Journal of Cancer, 84, 278-289
Open this publication in new window or tab >>Breast cancer in young women and prognosis: How important are proliferation markers?
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2017 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 84, p. 278-289Article in journal (Refereed) Published
Abstract [en]

Aim:

Compared to middle-aged women, young women with breast cancer have a higher risk of systemic disease. We studied expression of proliferation markers in relation to age and subtype and their association with long-term prognosis.

Methods:

Distant disease-free survival (DDFS) was studied in 504 women aged <40 years and 383 women aged >= 40 years from a population-based cohort. Information on patient characteristics, treatment and follow-up was collected from medical records. Tissue microarrays were produced for analysis of oestrogen receptor, progesterone receptor (PR), Her2, Ki-67 and cyclins.

Results:

Young women with luminal tumours had significantly higher expression of Ki-67 and cyclins. Proliferation markers were prognostic only within this subtype. Ki-67 was a prognostic indicator only in young women with luminal PR+ tumours. The optimal cut-off for Ki-67 varied by age. High expression of cyclin E1 conferred a better DDFS in women aged <40 years with luminal PR- tumours (hazard ratio [HR] 0.47 [0.24-0.92]). Age < 40 years was an independent risk factor of DDFS exclusively in women with luminal B PR+ tumours (HR 2.35 [1.22-4.50]). Young women with luminal B PR- tumours expressing low cyclin E1 had a six-fold risk of distant disease compared with luminal A ( HR 6.21 [2.17-17.6]).

Conclusions:

The higher expression of proliferation markers in young women does not have a strong impact on prognosis. Ki-67 is only prognostic in the subgroup of young women with luminal PR tumours. The only cyclin adding prognostic value beyond subtype is cyclin E1. Age is an independent prognostic factor only in women with luminal B PR+ tumours.

Keywords
Breast cancer, Young, Age, Subtype, Luminal, Progesterone receptor, Ki-67, Cyclin, Prognosis, Population-based
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-336293 (URN)10.1016/j.ejca.2017.07.044 (DOI)000411333300032 ()28844016 (PubMedID)
Available from: 2018-01-23 Created: 2018-01-23 Last updated: 2018-01-23Bibliographically approved
Magnusson, K., Gremel, G., Rydén, L., Pontén, V., Uhlén, M., Dimberg, A., . . . Pontén, F. (2016). ANLN is a prognostic biomarker independent of Ki-67 and essential for cell cycle progression in primary breast cancer. BMC Cancer, 16, Article ID 904.
Open this publication in new window or tab >>ANLN is a prognostic biomarker independent of Ki-67 and essential for cell cycle progression in primary breast cancer
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2016 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, article id 904Article in journal (Refereed) Published
Abstract [en]

Background: Anillin (ANLN), an actin-binding protein required for cytokinesis, has recently been presented as part of a prognostic marker panel in breast cancer. The objective of the current study was to further explore the prognostic and functional value of ANLN as a single biomarker in breast cancer. Methods: Immunohistochemical assessment of ANLN protein expression was performed in two well characterized breast cancer cohorts (n = 484) with long-term clinical follow-up data and the results were further validated at the mRNA level in a publicly available transcriptomics dataset. The functional relevance of ANLN was investigated in two breast cancer cell lines using RNA interference. Results: High nuclear fraction of ANLN in breast tumor cells was significantly associated with large tumor size, high histological grade, high proliferation rate, hormone receptor negative tumors and poor prognosis in both examined cohorts. Multivariable analysis showed that the association between ANLN and survival was significantly independent of age in cohort I and significantly independent of proliferation, as assessed by Ki-67 expression in tumor cells, age, tumor size, ER and PR status, HER2 status and nodal status in cohort II. Analysis of ANLN mRNA expression confirmed that high expression of ANLN was significantly correlated to poor overall survival in breast cancer patients. Consistent with the role of ANLN during cytokinesis, transient knock-down of ANLN protein expression in breast cancer cell lines resulted in an increase of senescent cells and an accumulation of cells in the G2/M phase of the cell cycle with altered cell morphology including large, poly-nucleated cells. Moreover, ANLN siRNA knockdown also resulted in decreased expression of cyclins D1, A2 and B1. Conclusions: ANLN expression in breast cancer cells plays an important role during cell division and a high fraction of nuclear ANLN expression in tumor cells is correlated to poor prognosis in breast cancer patients, independent of Ki-67, tumor size, hormone receptor status, HER2 status, nodal status and age.

Keywords
ANLN, Prognostic biomarker, Breast cancer, Proliferation, Antibody-based proteomics
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-264237 (URN)10.1186/s12885-016-2923-8 (DOI)000388038200007 ()
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer Society
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2017-12-01Bibliographically approved
Magnusson, K. (2015). Protein Expression Profiling of Cancer Biomarkers. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Protein Expression Profiling of Cancer Biomarkers
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Human Protein Atlas project is a Swedish research initiative that uses antibody-based proteomics for large scale protein profiling in human tissues and cells. Affinity-purified antibodies are produced within the project and used for immunohistochemical staining on tissue micro arrays (TMAs) in order to map the human proteome and publish the result in a protein atlas (www.proteinatlas.org). In this thesis, TMAs were used for analysis of protein expression patterns in order to identify and explore potential biomarkers of clinical relevance.

In Paper I, protein expression of SATB2 was studied in colorectal cancer. The results show that SATB2 is a sensitive and specific biomarker for colorectal cancer, staining 85% of all investigated tumors. Moreover, SATB2 in combination with CK20 showed positivity in 97% of all colorectal carcinomas and is therefore suitable as a complementary tool in clinical differential diagnostics of cancer.

In Paper II, ANLN was explored as a prognostic biomarker for breast cancer. A high nuclear fraction of ANLN in breast cancer was significantly correlated to large tumor size, high histological grade, hormone receptor negative tumors, high proliferation rate and poor prognosis. Furthermore, ANLN depletion in breast cancer cell lines resulted in cell cycle arrest and cellular senescence with altered cell morphology.

In Paper III, young age at breast cancer diagnosis was investigated as an independent risk factor for poor prognosis. TMAs were produced from a selection of patients from a previously defined register-based cohort. The analysis shows that young women with luminal B tumors have a 2.2-fold higher risk of dying of breast cancer compared to older women.

In Paper IV, vascular expression of CD93 was explored by image analysis of the tissue-based breast cancer cohort produced in Paper III. The analysis shows that young women with breast cancer display a significantly higher CD93-positive vessel area in their tumors. High CD93-positive vessel area was significantly associated with hormone receptor negative tumors, grade, Ki-67, EGFR and a poor prognosis.

In conclusion, this thesis shows that protein expression profiling using TMAs is an important tool for identifying and exploring potential novel biomarkers for cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1161
Keywords
Antibody-based proteomics, Biomarker, SATB2, Colorectal cancer, ANLN, Breast cancer, CD93, Angiogenesis
National Category
Basic Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-265513 (URN)978-91-554-9404-9 (ISBN)
Public defence
2015-12-18, Rudbeck hall, Rudbeck laboratory, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
Opponent
Supervisors
Funder
Knut and Alice Wallenberg Foundation
Available from: 2015-11-27 Created: 2015-10-30 Last updated: 2018-01-10
Fredholm, H., Magnusson, K., Lindstrom, L. S., Garmo, H., Eaker, S., Lindman, H., . . . Fredriksson, I. (2014). Breast cancer in young women - age a risk factor only in those not given chemotherapy. Paper presented at BCY2 - 2nd Breast Cancer in Young Women Conference04/11/2014 - 05/11/2014, Dublin, Ireland. Breast, 23(S1), S12-S12, Article ID HM31.
Open this publication in new window or tab >>Breast cancer in young women - age a risk factor only in those not given chemotherapy
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2014 (English)In: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 23, no S1, p. S12-S12, article id HM31Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-246868 (URN)10.1016/S0960-9776(14)70041-4 (DOI)000347594900029 ()
Conference
BCY2 - 2nd Breast Cancer in Young Women Conference04/11/2014 - 05/11/2014, Dublin, Ireland
Available from: 2015-03-11 Created: 2015-03-11 Last updated: 2017-12-04Bibliographically approved
Cepeda, D., Ng, H.-F., Sharifi, H. R., Mahmoudi, S., Soto Cerrato, V., Fredlund, E., . . . Sangfelt, O. (2013). CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer. EMBO Molecular Medicine, 5(7), 1067-1086
Open this publication in new window or tab >>CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
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2013 (English)In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 5, no 7, p. 1067-1086Article in journal (Refereed) Published
Abstract [en]

SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer.

Keywords
Breast cancer, CDK, F-box protein, FBXO28, MYC
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211910 (URN)10.1002/emmm.201202341 (DOI)000325942300009 ()
Available from: 2013-12-03 Created: 2013-12-03 Last updated: 2017-12-06Bibliographically approved
Magnusson, K., Gremel, G., Ponten, F. & Jirstrom, K. (2013). Expression of the actin-binding protein Anillin is a prognostic biomarker for primary ER positive breast cancer.. Paper presented at 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), APR 06-10, 2013, Washington, DC. Cancer Research, 73(8), S1
Open this publication in new window or tab >>Expression of the actin-binding protein Anillin is a prognostic biomarker for primary ER positive breast cancer.
2013 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8, p. S1-Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-221211 (URN)10.1158/1538-7445.AM2013-390 (DOI)000331212900354 ()
Conference
104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), APR 06-10, 2013, Washington, DC
Available from: 2014-03-26 Created: 2014-03-26 Last updated: 2017-12-05Bibliographically approved
Uhlen, M., Bjorling, E., Agaton, C., Szigyarto, C.-K. A., Amini, B., Andersen, E., . . . Pontén, F. (2005). A human protein atlas for normal and cancer tissues based on antibody proteomics. Molecular & Cellular Proteomics, 4(12), 1920-1932
Open this publication in new window or tab >>A human protein atlas for normal and cancer tissues based on antibody proteomics
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2005 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 4, no 12, p. 1920-1932Article in journal (Refereed) Published
Abstract [en]

Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, ∼400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.

Keywords
Antibodies/*chemistry/isolation & purification, Antibodies; Neoplasm/*chemistry/isolation & purification, Blotting; Western, Chromatography; Affinity, Databases; Protein, Epitopes/chemistry, Expressed Sequence Tags, Humans, Neoplasms/genetics/*immunology, Proteins/immunology, Proteome/*immunology/isolation & purification, Reference Values, Research Support; Non-U.S. Gov't
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-80605 (URN)10.1074/mcp.M500279-MCP200 (DOI)16127175 (PubMedID)
Available from: 2007-04-18 Created: 2007-04-18 Last updated: 2018-12-10Bibliographically approved
Magnusson, K., Fredholm, H., Georganaki, M., Uhlén, M., Fredriksson, I., Dimberg, A. & Pontén, F.Angiogenesis as a risk factor for young women with breast cancer.
Open this publication in new window or tab >>Angiogenesis as a risk factor for young women with breast cancer
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(English)Manuscript (preprint) (Other academic)
Keywords
Angiogenesis, CD93, Prognostic biomarker, Breast cancer, Antibody-based proteomics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-264226 (URN)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2016-01-13
Fredholm, H., Magnusson, K., Lindström, L., Garmo, H., Eaker Fält, S., Lindman, H., . . . Fredriksson, I. Longterm outcomes in young women with breast cancer – low age a risk factor in luminal B tumors.
Open this publication in new window or tab >>Longterm outcomes in young women with breast cancer – low age a risk factor in luminal B tumors
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(English)Article in journal (Other academic) Submitted
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-264243 (URN)
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2016-01-13
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6386-2260

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