| 1. |
- Aydoğdu, Eylem, et al.
(författare)
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MicroRNA-regulated gene networks during mammary cell differentiation are associated with breast cancer.
- 2012
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 33:8, s. 1502-11
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) play pivotal roles in stem cell biology, differentiation and oncogenesis and are of high interest as potential breast cancer therapeutics. However, their expression and function during normal mammary differentiation and in breast cancer remain to be elucidated. In order to identify which miRNAs are involved in mammary differentiation, we thoroughly investigated miRNA expression during functional differentiation of undifferentiated, stem cell-like, murine mammary cells using two different large-scale approaches followed by qPCR. Significant changes in expression of 21 miRNAs were observed in repeated rounds of mammary cell differentiation. The majority, including the miR-200 family and known tumor suppressor miRNAs, was upregulated during differentiation. Only four miRNAs, including oncomiR miR-17, were downregulated. Pathway analysis indicated complex interactions between regulated miRNA clusters and major pathways involved in differentiation, proliferation and stem cell maintenance. Comparisons with human breast cancer tumors showed the gene profile from the undifferentiated, stem-like stage clustered with that of poor-prognosis breast cancer. A common nominator in these groups was the E2F pathway, which was overrepresented among genes targeted by the differentiation-induced miRNAs. A subset of miRNAs could further discriminate between human non-cancer and breast cancer cell lines, and miR-200a/miR-200b, miR-146b and miR-148a were specifically downregulated in triple-negative breast cancer cells. We show that miR-200a/miR-200b can inhibit epithelial-mesenchymal transition (EMT)-characteristic morphological changes in undifferentiated, non-tumorigenic mammary cells. Our studies propose EphA2 as a novel and important target gene for miR-200a. In conclusion, we present evidentiary data on how miRNAs are involved in mammary cell differentiation and indicate their related roles in breast cancer.
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| 2. |
- Granskog, Viktor, et al.
(författare)
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Linear Dendritic Block Copolymers as Promising Biomaterials for the Manufacturing of Soft Tissue Adhesive Patches Using Visible Light Initiated Thiol-Ene Coupling Chemistry
- 2015
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Ingår i: Advanced Functional Materials. - : Wiley-VCH Verlagsgesellschaft. - 1616-301X .- 1616-3028. ; 25:42, s. 6596-6605
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Tidskriftsartikel (refereegranskat)abstract
- A library of dendritic-linear-dendritic (DLD) materials comprising linear poly(ethylene glycol) and hyperbranched dendritic blocks based on 2,2-bis(hydroxymethyl) propionic acid is successfully synthesized and post-functionalized with peripheral allyl groups. Reactive DLDs with pseudo-generations of 3 to 6 (G3-G6) are isolated in large scale allowing their thorough evaluation as important components for the development of biomedical adhesives. Due to their branched nature and inherent degradable ester-bonds, promising biomaterial resins are accomplished with suitable viscosity, eliminating the excessive use of co-solvents. By utilizing benign high-energy visible light initiated thiol-ene coupling chemistry, DLDs together with tris[2-(3-mercaptopropionyloxy) ethyl] isocyanurate and surgical mesh enable the fabrication of soft tissue adhesive patches (STAPs) within a total irradiation time of 30 s. The STAPs display the ability to create good adhesion to wet soft tissue and encouraging results in cytotoxicity tests. All crosslinked materials are also found to degrade after being stored in human blood plasma and phosphate buffered saline. The proposed benign methodology coupled with the promising features of the crosslinked materials is herein envisioned as a soft tissue adhesive with properties that do not exist in currently available tissue adhesives.
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| 3. |
- Jia, Min, et al.
(författare)
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Estrogen Receptor a Promotes Breast Cancer by Reprogramming Choline Metabolism
- 2016
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 76:19, s. 5634-5646
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor alpha (ER alpha) is a key regulator of breast growth and breast cancer development. Here, we report how ER alpha impacts these processes by reprogramming metabolism in malignant breast cells. We employed an integrated approach, combining genome-wide mapping of chromatin-bound ER alpha with estrogeninduced transcript and metabolic profiling, to demonstrate that ER alpha reprograms metabolism upon estrogen stimulation, including changes in aerobic glycolysis, nucleotide and amino acid synthesis, and choline (Cho) metabolism. Cho phosphotransfse CHPT1, identified as a direct era-regulated gene, was required for estrogen- induced effects on Cho metabolism, including increased phosphatidylcholine synthesis. CHPT1 silencing inhibited anchorage- independent growth and cell proliferation, also suppressing early-stage metastasis of tamoxifen-resistant breast cancer cells in a zebrafish xenograft model. Our results showed that era promotes metabolic alterations in breast cancer cells mediated by its target CHPT1, which this study implicates as a candidate therapeutic target. (C) 2016 AACR.
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| 4. |
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| 5. |
- Sivik, Tove, 1980-
(författare)
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Elucidating the role of 17β hydroxysteroid dehydrogenase type 14 in normal physiology and in breast cancer
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Oestrogens play key roles in the development of the majority of breast tumours, a fact that has been exploited successfully in treating breast cancer with tamoxifen, which is a selective oestrogen receptor modulator. In post-menopausal women, oestrogens are synthesised in peripheral hormone-target tissues from adrenally derived precursors. Important in the peripheral fine-tuning of sex hormone levels are the 17β hydroxysteroid dehydrogenases (17βHSDs). These enzymes catalyse the oxidation/reduction of carbon 17β of androgens and oestrogens. Upon receptor binding, the 17β-hydroxy conformation of androgens and oestrogens (testosterone and oestradiol) triggers a greater biological response than the corresponding keto-conformation of the steroids (androstenedione and oestrone), and the 17βHSD enzymes are therefore important mediators in pre-receptor regulation of sex hormone action.Breast tumours differ substantially with regards to molecular and/or biochemical signatures and thus clinical courses and response to treatment. Predictive factors, which aim to foretell the response of a patient to a specific therapeutic intervention, are therefore important tools for individualisation of breast cancer therapy. This thesis focuses on 17βHSD14, which is one such proposed marker, aiming to learn more of properties of the enzyme in breast cancer as well as in normal physiology. We found that high 17βHSD14 levels were correlated with clinical outcome in two separate subsets of breast tumour materials from trials evaluating adjuvant tamoxifen therapy. Striving to understand the underlying mechanisms, immunohistochemical 17βHSD14 expression patterns were analysed in a large number of human tissues using an in-house generated and validated antibody. The 17βHSD14 protein was expressed in several classical steroidogenic tissues such as breast, ovary and testis which supports idea of 17βHSD14 being an actor in sex steroid interconversion. Furthermore, using a radio-high pressure liquid chromatography method, cultured cells transiently expressing HSD17B14 were found to oxidise both oestradiol and testosterone to their less potent metabolites oestrone and androstenedione respectively. The evaluation of a mouse model lacking Hsd17b14 revealed a phenotype with impaired mammary gland branching and hepatic vacuolisation which could further suggest a role for 17βHSD14 in oestrogen regulation.Although other mechanisms of the enzyme cannot be ruled out, we suggest that 17βHSD14 relevance in tamoxifen-treated breast cancer is related to oestradiol-lowering properties of the enzyme which potentiate the anti-proliferative effects of tamoxifen. Translating into the clinical setting, patients with oestrogen receptor positive tumours expressing low levels of oestradiol-oxidising enzymes such as 17βHSD14 would likely receive more clinical benefit from alternative treatments to tamoxifen such as aromatase inhibitors or in the future possibly inhibitors of reductive 17βHSD-enzymes.
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| 6. |
- Song, Dandan, et al.
(författare)
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Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor
- 2021
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 506, s. 23-34
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Tidskriftsartikel (refereegranskat)abstract
- The AP-1 member Fra-1 is overexpressed in TNBC and plays crucial roles in tumor progression and treatment resistance. In a previous large-scale screen, we identified PARP1 to be among 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells. PARP1 inhibitor (olaparib) is currently in clinical use for treatment of BRCA-mutated TNBC breast cancer. Here, we demonstrate that the Fra-1-PARP1 interaction impacts the efficacy of olaparib treatment. We show that PARP1 interacts with and downregulates Fra-1, thereby reducing AP-1 transcriptional activity. Olaparib treatment, or silencing of PARP1, consequently, increases Fra-1 levels and enhances its transcriptional activity. Increased Fra-1 can have adverse effect, including treatment resistance. We also found that a large fraction of PARP1-regulated genes was dependent on Fra-1. We show that by inhibiting Fra-1/AP-1, non-BRCA-mutated TNBC cells can become sensitized to olaparib treatment. We identify that high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall (P = 0.01), but not for HER-2 positive patients. In conclusion, by exploring the functionality of the Fra-1 and PARP1 interaction, we propose that targeting Fra-1 could serve as a combinatory therapeutic approach to improve olaparib treatment outcome for TNBC patients.
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| 7. |
- Song, Dandan, et al.
(författare)
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ER alpha and ER beta Homodimers in the Same Cellular Context Regulate Distinct Transcriptomes and Functions
- 2022
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The two estrogen receptors ER alpha and ER beta are nuclear receptors that bind estrogen (E2) and function as ligand-inducible transcription factors. They are homologues and can form dimers with each other and bind to the same estrogen-response element motifs in the DNA. ER alpha drives breast cancer growth whereas ER beta has been reported to be anti-proliferative. However, they are rarely expressed in the same cells, and it is not fully investigated to which extent their functions are different because of inherent differences or because of different cellular context. To dissect their similarities and differences, we here generated a novel estrogen-dependent cell model where ER alpha homodimers can be directly compared to ER beta homodimers within the identical cellular context. By using CRISPR-cas9 to delete ER alpha in breast cancer MCF7 cells with Tet-Off-inducible ER beta expression, we generated MCF7 cells that express ER beta but not ER alpha. MCF7 (ER beta only) cells exhibited regulation of estrogen-responsive targets in a ligand-dependent manner. We demonstrated that either ER was required for MCF7 proliferation, but while E2 increased proliferation via ER alpha, it reduced proliferation through a G2/M arrest via ER beta. The two ERs also impacted migration differently. In absence of ligand, ER beta increased migration, but upon E2 treatment, ER beta reduced migration. E2 via ER alpha, on the other hand, had no significant impact on migration. RNA sequencing revealed that E2 regulated a transcriptome of around 800 genes via each receptor, but over half were specific for either ER alpha or ER beta (417 and 503 genes, respectively). Functional gene ontology enrichment analysis reinforced that E2 regulated cell proliferation in opposite directions depending on the ER, and that ER beta specifically impacted extracellular matrix organization. We corroborated that ER beta bound to cis-regulatory chromatin of its unique proposed migration-related direct targets ANXA9 and TFAP2C. In conclusion, we demonstrate that within the same cellular context, the two ERs regulate cell proliferation in the opposite manner, impact migration differently, and each receptor also regulates a distinct set of target genes in response to E2. The developed cell model provides a novel and valuable resource to further complement the mechanistic understanding of the two different ER isoforms.
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| 8. |
- Williams, Cecilia, 1969-, et al.
(författare)
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Gene expression in murine mammary epithelial stem cell-like cells shows similarities to human breast cancer gene expression.
- 2009
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Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X. ; 11:3, s. R26-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Mammary stem cells are bipotential and suggested to be the origin of breast cancer development, but are elusive and vaguely characterized. Breast tumors can be divided into subgroups, each one requiring specific treatment. To determine a possible association between mammary stem cells and breast cancer, a detailed characterization of the transcriptome in mammary stem cells is essential.METHODS: We have used a murine mammary epithelial stem-like cell line (HC11) and made a thorough investigation of global gene-expression changes during stepwise differentiation using dual-color comparative microarray technique. Subsequently, we have performed a cross-species comparison to reveal conserved gene expression between stem cells and subtype-specific and prognosis gene signatures, and correlated gene expression to in vivo mammary gland development.RESULTS: Our analysis of mammary stem-like and stepwise cell differentiation, and an in-depth description of our findings in a breast cancer perspective provide a unique map of the transcriptomic changes and a number of novel mammary stem cell markers. We correlate the alterations to in vivo mammary gland differentiation, and describe novel changes in nuclear receptor gene expression. Interestingly, our comparisons show that specific subtypes of breast cancers with poor prognosis and metastasizing capabilities show resemblance to stem-like gene expression.CONCLUSIONS: The transcriptional characterization of these mammary stem-like cells and their differentiation-induced gene expression patterns is here made widely accessible and provides a basis for research on mammary stem-like cells. Our comparisons suggest that some tumors are more stem-like than others, with a corresponding worse prognosis. This information would, if established, be important for treatment decisions. We also suggest several marker candidates valuable to investigate further.
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