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Publications (10 of 33) Show all publications
Danielsson, F., Fasterius, E., Sullivan, D., Hases, L., Sanli, K., Zhang, C., . . . Lundberg, E. (2018). Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia. OncoTarget, 9(28), 19730-19744
Open this publication in new window or tab >>Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia
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2018 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 28, p. 19730-19744Article in journal (Refereed) Published
Abstract [en]

In tumor tissues, hypoxia is a commonly observed feature resulting from rapidly proliferating cancer cells outgrowing their surrounding vasculature network. Transformed cancer cells are known to exhibit phenotypic alterations, enabling continuous proliferation despite a limited oxygen supply. The four-step isogenic BJ cell model enables studies of defined steps of tumorigenesis: the normal, immortalized, transformed, and metastasizing stages. By transcriptome profiling under atmospheric and moderate hypoxic (3% O2) conditions, we observed that despite being highly similar, the four cell lines of the BJ model responded strikingly different to hypoxia. Besides corroborating many of the known responses to hypoxia, we demonstrate that the transcriptome adaptation to moderate hypoxia resembles the process of malignant transformation. The transformed cells displayed a distinct capability of metabolic switching, reflected in reversed gene expression patterns for several genes involved in oxidative phosphorylation and glycolytic pathways. By profiling the stage-specific responses to hypoxia, we identified ASS1 as a potential prognostic marker in hypoxic tumors. This study demonstrates the usefulness of the BJ cell model for highlighting the interconnection of pathways involved in malignant transformation and hypoxic response.

Place, publisher, year, edition, pages
Impact Journals LLC, 2018
Keywords
Hypoxia, Malignant transformation, Transcriptomics
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-227616 (URN)10.18632/oncotarget.24808 (DOI)2-s2.0-85045315705 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20180522

Available from: 2018-05-22 Created: 2018-05-22 Last updated: 2018-05-22Bibliographically approved
Andersson, S., Sundberg, M., Pristovsek, N., Ibrahim, A., Jonsson, P., Katona, B., . . . Asplund, A. (2017). Insufficient antibody validation challenges oestrogen receptor beta research. Nature Communications, 8, Article ID 15840.
Open this publication in new window or tab >>Insufficient antibody validation challenges oestrogen receptor beta research
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15840Article in journal (Refereed) Published
Abstract [en]

The discovery of oestrogen receptor beta (ER beta/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ER alpha (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ER beta antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ER beta in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ER beta protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Nano Technology
Identifiers
urn:nbn:se:kth:diva-210349 (URN)10.1038/ncomms15840 (DOI)000403317200001 ()2-s2.0-85020892431 (Scopus ID)
Note

QC 20170704

Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2017-11-29Bibliographically approved
Williams, C., DiLeo, A., Niv, Y. & Gustafsson, J.-A. (2016). Estrogen receptor beta as target for colorectal cancer prevention. Cancer Letters, 372(1), 48-56
Open this publication in new window or tab >>Estrogen receptor beta as target for colorectal cancer prevention
2016 (English)In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 372, no 1, p. 48-56Article, review/survey (Refereed) Published
Abstract [en]

Colorectal cancer (CRC) is a leading cause of death in the United States. Despite its slow development and the capacity for early diagnosis, current preventive approaches are not sufficient. However, a role for estrogen has been demonstrated in multiple epidemiologic studies, which may benefit CRC prevention. A large body of evidence from preclinical studies indicates that expression of the estrogen receptor beta (ER beta/ESR2) demonstrates an inverse relationship with the presence of colorectal polyps and stage of tumors, and can mediate a protective response. Natural compounds, including phytoestrogens, or synthetic ER beta selective agonists, can activate or upregulate ER beta in the colon and promote apoptosis in preclinical models and in clinical experience. Importantly, this activity has been associated with a reduction in polyp formation and, in rodent models of CRC, has been shown to lower incidence of colon adenocarcinoma. Collectively, these findings indicate that targeted activation of ER beta may represent a novel clinical approach for management of colorectal adenomatous polyps and prevention of colorectal carcinoma in patients at risk for this condition. In this review, we discuss the potential of new chemopreventive or dietary approaches based on estrogen signaling.

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
Colorectal cancer, Estrogen, Estrogen receptor beta, Phytoestrogens, Prevention, Gene expression
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:kth:diva-184022 (URN)10.1016/j.canlet.2015.12.009 (DOI)000370832600005 ()26708506 (PubMedID)2-s2.0-84958213395 (Scopus ID)
Note

QC 20160324

Available from: 2016-03-24 Created: 2016-03-22 Last updated: 2017-11-30Bibliographically approved
Katchy, A. & Williams, C. (2016). Expression Profiles of Estrogen-Regulated MicroRNAs in Breast Cancer Cells. In: Kathleen M. Eyster (Ed.), Methods in Molecular Biology: The Estrogen Receptors. Springer, 1366
Open this publication in new window or tab >>Expression Profiles of Estrogen-Regulated MicroRNAs in Breast Cancer Cells
2016 (English)In: Methods in Molecular Biology: The Estrogen Receptors / [ed] Kathleen M. Eyster, Springer, 2016, Vol. 1366Chapter in book (Other academic)
Abstract [en]

Molecular signaling through both estrogen and microRNAs are critical for breast cancer development and growth. The activity of estrogen is mediated by transcription factors, the estrogen receptors. Here we describe a method for robust characterization of estrogen-regulated microRNA profiles. The method details how to prepare cells for optimal estrogen response, directions for estrogen treatment, RNA extraction, microRNA large-scale profiling, and subsequent confirmations.

Place, publisher, year, edition, pages
Springer, 2016
Keywords
Receptor Tyrosine Kinase, Mammary Epithelial-Cells, Activated Protein-Kinase, Mesenchymal Transition, Posttranscriptional Regulation, Gene-Expression, Stem-Cells, Microrna, Progression, Family
National Category
Natural Sciences Biological Sciences Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-178111 (URN)10.1007/978-1-4939-3127-9_30 (DOI)26585151 (PubMedID)2-s2.0-84947781743 (Scopus ID)
Note

QC 20151214

Available from: 2015-12-07 Created: 2015-12-07 Last updated: 2018-01-10Bibliographically approved
Reins, R. Y., Mesmar, F., Williams, C. & McDermott, A. M. (2016). Microarray Analysis of Vitamin D Treated Human Corneal Epithelial Cells. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-05, 2016, Seattle, WA. Investigative Ophthalmology and Visual Science, 57(12)
Open this publication in new window or tab >>Microarray Analysis of Vitamin D Treated Human Corneal Epithelial Cells
2016 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 12Article in journal (Refereed) Published
Place, publisher, year, edition, pages
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2016
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-204141 (URN)000394210205172 ()
Conference
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-05, 2016, Seattle, WA
Note

QC 20170328

Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2017-11-29Bibliographically approved
Zhu, J., Zhao, C., Zhuang, T., Jonsson, P., Sinha, I., Williams, C., . . . Dahlman-Wright, K. (2016). RING finger protein 31 promotes p53 degradation in breast cancer cells. Oncogene, 35(15), 1955-1964
Open this publication in new window or tab >>RING finger protein 31 promotes p53 degradation in breast cancer cells
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2016 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 15, p. 1955-1964Article in journal (Refereed) Published
Abstract [en]

The atypical E3 ubiquitin ligase RNF31 is highly expressed in human breast cancer, the most frequent neoplastic lethality among women. Here, RNF31 depletion in breast cancer cells in combination with global gene expression profiling revealed p53 (TP53) signaling as a potential RNF31 target. Interestingly, RNF31 decreased p53 stability, whereas depletion of RNF31 in breast cancer cells caused cell cycle arrest and cisplatin-induced apoptosis in a p53-dependent manner. Furthermore, RNF31 associated with the p53/MDM2 complex and facilitated p53 polyubiquitination and degradation by stabilizing MDM2, suggesting a molecular mechanism by which RNF31 regulates cell death. Analysis of publically available clinical data sets displayed a negative correlation between RNF31 and p53 target genes, including IGFBP3 and BTG1, consistent with RNF31 regulating p53 function in vivo as well. Together, our findings suggest RNF31 as a potential therapeutic target to restore p53 function in breast cancer.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
Keywords
ESTROGEN-RECEPTOR-ALPHA, MDM2 ANTAGONIST NUTLIN-3, UBIQUITIN LIGASE ACTIVITY, TRANSCRIPTIONAL REPRESSION, GERMLINE POLYMORPHISMS, ONCOPROTEIN MDM2, APOPTOSIS, E3, ACTIVATION, MUTATIONS
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-186617 (URN)10.1038/onc.2015.260 (DOI)000374010300008 ()26148235 (PubMedID)2-s2.0-84935442275 (Scopus ID)
Note

QC 20160531

Available from: 2016-05-31 Created: 2016-05-13 Last updated: 2018-01-10Bibliographically approved
Dey, P., Velazquez-Villegas, L. A., Faria, M., Turner, A., Jonsson, P., Webb, P., . . . Ström, A. M. (2015). Estrogen Receptor beta 2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1 alpha in Prostate Cancer. PLoS ONE, 10(5), Article ID e0128239.
Open this publication in new window or tab >>Estrogen Receptor beta 2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1 alpha in Prostate Cancer
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0128239Article in journal (Refereed) Published
Abstract [en]

The estrogen receptor (ER) beta variant ER beta 2 is expressed in aggressive castration-resistant prostate cancer and has been shown to correlate with decreased overall survival. Genome-wide expression analysis after ER beta 2 expression in prostate cancer cells revealed that hypoxia was an overrepresented theme. Here we show that ER beta 2 interacts with and stabilizes HIF-1 alpha protein in normoxia, thereby inducing a hypoxic gene expression signature. HIF-1 alpha is known to stimulate metastasis by increasing expression of Twist1 and increasing vascularization by directly activating VEGF expression. We found that ER beta 2 interacts with HIF-1 alpha and piggybacks to the HIF-1 alpha response element present on the proximal Twist1 and VEGF promoters. These findings suggest that at least part of the oncogenic effects of ER beta 2 is mediated by HIF-1 alpha and that targeting of this ER beta 2 -HIF-1 alpha interaction may be a strategy to treat prostate cancer.

Keywords
Tumor-Suppressor Protein, Hippel-Lindau Protein, Androgen Receptor, Er-Beta, Alpha, Growth, Hif, Transcription, Metastasis, Mechanism
National Category
Biological Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-169966 (URN)10.1371/journal.pone.0128239 (DOI)000355183900212 ()26010887 (PubMedID)2-s2.0-84930221880 (Scopus ID)
Funder
Swedish Cancer SocietyEU, FP7, Seventh Framework Programme, GROWTH 291795Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20150625

Available from: 2015-06-25 Created: 2015-06-25 Last updated: 2017-12-04Bibliographically approved
Bondesson, M., Hao, R., Lin, C.-Y., Williams, C. & Gustafsson, J.-Å. (2015). Estrogen receptor signaling during vertebrate development. Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, 1849(2), 142-151
Open this publication in new window or tab >>Estrogen receptor signaling during vertebrate development
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2015 (English)In: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, ISSN 1874-9399, E-ISSN 1876-4320, Vol. 1849, no 2, p. 142-151Article, review/survey (Refereed) Published
Abstract [en]

Estrogen receptors are expressed and their cognate ligands produced in all vertebrates, indicative of important and conserved functions. Through evolution estrogen has been involved in controlling reproduction, affecting both the development of reproductive organs and reproductive behavior. This review broadly describes the synthesis of estrogens and the expression patterns of aromatase and the estrogen receptors, in relation to estrogen functions in the developing fetus and child. We focus on the role of estrogens for the development of reproductive tissues, as well as non-reproductive effects on the developing brain. We collate data from human, rodent, bird and fish studies and highlight common and species-specific effects of estrogen signaling on fetal development. Morphological malformations originating from perturbed estrogen signaling in estrogen receptor and aromatase knockout mice are discussed, as well as the clinical manifestations of rare estrogen receptor alpha and aromatase gene mutations in humans.

Keywords
Estrogen, Aromatase, Estrogen receptor, Reproductive development, Sex differentiation, Vertebrate development
National Category
Health Sciences Cell and Molecular Biology
Research subject
SRA - Molecular Bioscience
Identifiers
urn:nbn:se:kth:diva-165366 (URN)10.1016/j.bbagrm.2014.06.005 (DOI)000349272700008 ()24954179 (PubMedID)2-s2.0-84921023929 (Scopus ID)
Funder
Swedish Cancer Society
Note

QC 20150512

Available from: 2015-04-27 Created: 2015-04-27 Last updated: 2018-01-11Bibliographically approved
Tsouko, E., Wang, J., Frigo, D. E., Aydogdu, E. & Williams, C. (2015). miR-200a inhibits migration of triple-negative breast cancer cells through direct repression of the EPHA2 oncogene. Carcinogenesis, 36(9), 1051-1060
Open this publication in new window or tab >>miR-200a inhibits migration of triple-negative breast cancer cells through direct repression of the EPHA2 oncogene
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2015 (English)In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 36, no 9, p. 1051-1060Article in journal (Refereed) Published
Abstract [en]

Triple-negative breast cancer (TNBC) is characterized by aggressiveness and affects 10-20% of breast cancer patients. Since TNBC lacks expression of ER alpha, PR and HER2, existing targeted treatments are not effective and the survival is poor. In this study, we demonstrate that the tumor suppressor microRNA miR-200a directly regulates the oncogene EPH receptor A2 (EPHA2) and modulates TNBC migration. We show that EPHA2 expression is correlated with poor survival specifically in basal-like breast cancer and that its expression is repressed by miR-200a through direct interaction with the 3'UTR of EPHA2. This regulation subsequently affects the downstream activation of AMP-activated protein kinase (AMPK) and results in decreased cell migration of TNBC. We establish that miR-200a directs cell migration in a dual manner; in addition to regulating the well-characterized E-cadherin pathway it also regulates a EPHA2 pathway. The miR-200a-EPHA2 axis is a novel mechanism highlighting the possibility of utilizing miR-200a delivery to target TNBC metastases.

Place, publisher, year, edition, pages
Oxford University Press, 2015
Keywords
Receptor Tyrosine Kinase, Mammary Epithelial-Cells, Activated Protein-Kinase, Mesenchymal Transition, Posttranscriptional Regulation, Gene-Expression, Stem-Cells, Microrna, Progression, Family
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-174928 (URN)10.1093/carcin/bgv087 (DOI)000361397000013 ()26088362 (PubMedID)2-s2.0-84940670729 (Scopus ID)
Note

QC 20151022

Available from: 2015-10-22 Created: 2015-10-09 Last updated: 2018-01-11Bibliographically approved
Jonsson, P., Coarfa, C., Mesmar, F., Raz, T., Rajapakshe, K., Thompson, J. F., . . . Williams, C. (2015). Single-Molecule Sequencing Reveals Estrogen-Regulated Clinically Relevant lncRNAs in Breast Cancer. Molecular Endocrinology, 29(11)
Open this publication in new window or tab >>Single-Molecule Sequencing Reveals Estrogen-Regulated Clinically Relevant lncRNAs in Breast Cancer
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2015 (English)In: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 29, no 11Article in journal (Refereed) Published
Abstract [en]

Estrogen receptor (ER)α-positive tumors are commonly treated with ERα antagonists or inhibitors of estrogen synthesis, but most tumors develop resistance, and we need to better understand the pathways that underlie the proliferative and tumorigenic role of this estrogen-activated transcription factor. We here present the first single-molecule sequencing of the estradiol-induced ERα transcriptome in the luminal A-type human breast cancer cell lines MCF7 and T47D. Sequencing libraries were prepared from the polyadenylated RNA fraction after 8 hours of estrogen or vehicle treatment. Single-molecule sequencing was carried out in biological and technical replicates and differentially expressed genes were defined and analyzed for enriched processes. Correlation analysis with clinical expression and survival were performed, and follow-up experiments carried out using time series, chromatin immunoprecipitation and quantitative real-time PCR. We uncovered that ERα in addition to regulating approximately 2000 protein-coding genes, also regulated up to 1000 long noncoding RNAs (lncRNAs). Most of these were up-regulated, and 178 lncRNAs were regulated in both cell lines. We demonstrate that Long Intergenic Non-protein Coding RNA 1016 (LINC01016) and LINC00160 are direct transcriptional targets of ERα, correlate with ERα expression in clinical samples, and show prognostic significance in relation to breast cancer survival. We show that silencing of LINC00160 results in reduced proliferation, demonstrating that lncRNA expression have functional consequences. Our findings suggest that ERα regulation of lncRNAs is clinically relevant and that their functions and potential use as biomarkers for endocrine response are important to explore.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-178113 (URN)10.1210/me.2015-1153 (DOI)000366510200010 ()26426411 (PubMedID)2-s2.0-84946057420 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20151214

Available from: 2015-12-07 Created: 2015-12-07 Last updated: 2018-01-10Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0602-2062

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