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Protein Expression Profiling of Cancer Biomarkers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Fredrik Pontén)ORCID iD: 0000-0002-6386-2260
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. , 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1161
Keyword [en]
Antibody-based proteomics, Biomarker, SATB2, Colorectal cancer, ANLN, Breast cancer, CD93, Angiogenesis
National Category
Basic Medicine
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-265513ISBN: 978-91-554-9404-9 (print)OAI: oai:DiVA.org:uu-265513DiVA: diva2:866185
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: 2016-01-13
List of papers
1. SATB2 in Combination With Cytokeratin 20 Identifies Over 95% of all Colorectal Carcinomas
Open this publication in new window or tab >>SATB2 in Combination With Cytokeratin 20 Identifies Over 95% of all Colorectal Carcinomas
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2011 (English)In: American Journal of Surgical Pathology, ISSN 0147-5185, E-ISSN 1532-0979, Vol. 35, no 7, 937-948 p.Article in journal (Refereed) Published
Abstract [en]

The special AT-rich sequence-binding protein 2 (SATB2), a nuclear matrix-associated transcription factor and epigenetic regulator, was identified as a tissue type-specific protein when screening protein expression patterns in human normal and cancer tissues using an antibody-based proteomics approach. In this respect, the SATB2 protein shows a selective pattern of expression and, within cells of epithelial lineages, SATB2 expression is restricted to glandular cells lining the lower gastrointestinal tract. The expression of SATB2 protein is primarily preserved in cancer cells of colorectal origin, indicating that SATB2 could function as a clinically useful diagnostic marker to distinguish colorectal cancer (CRC) from other types of cancer. The aim of this study was to further explore and validate the specific expression pattern of SATB2 as a clinical biomarker and to compare SATB2 with the well-known cytokeratin 20 (CK20). Immunohistochemistry was used to analyze the extent of SATB2 expression in tissue microarrays with tumors from 9 independent cohorts of patients with primary and metastatic CRCs (n = 1882). Our results show that SATB2 is a sensitive and highly specific marker for CRC with distinct positivity in 85% of all CRCs, and that SATB2 and/or CK20 was positive in 97% of CRCs. In conclusion, the specific expression of SATB2 in a large majority of CRCs suggests that SATB2 can be used as an important complementary tool for the differential diagnosis of carcinoma of unknown primary origin.

Keyword
SATB2, colorectal cancer, antibody-based proteomics, diagnostic biomarker
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-156012 (URN)10.1097/PAS.0b013e31821c3dae (DOI)000291676200001 ()
Available from: 2011-07-05 Created: 2011-07-05 Last updated: 2017-12-11Bibliographically approved
2. ANLN is a prognostic biomarker independent of Ki-67 and essential for cell cycle progression in primary breast cancer
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, 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.

Keyword
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
3. 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
4. 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)
Keyword
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

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