103 results on '"Pauliina Kronqvist"'
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2. Lääkärin ammatillinen kutsumus terveydenhuollon ja työelämän muutoksessa
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Pauliina Kronqvist
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Labor. Work. Working class ,HD4801-8943 ,Business ,HF5001-6182 - Published
- 2022
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3. ADAM17-mediated EGFR ligand shedding directs macrophage-promoted cancer cell invasion
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Sebastian P. Gnosa, Laia Puig Blasco, Krzysztof B. Piotrowski, Marie L. Freiberg, Simonas Savickas, Daniel H. Madsen, Ulrich auf dem Keller, Pauliina Kronqvist, and Marie Kveiborg
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Oncology ,Medicine - Abstract
Macrophages in the tumor microenvironment have a substantial impact on tumor progression. Depending on the signaling environment in the tumor, macrophages can either support or constrain tumor progression. It is therefore of therapeutic interest to identify the tumor-derived factors that control macrophage education. With this aim, we correlated the expression of A Disintegrin and Metalloproteinase (ADAM) proteases, which are key mediators of cell-cell signaling, to the expression of protumorigenic macrophage markers in human cancer cohorts. We identified ADAM17, a sheddase upregulated in many cancer types, as a protein of interest. Depletion of ADAM17 in cancer cell lines reduced the expression of several protumorigenic markers in neighboring macrophages in vitro as well as in mouse models. Moreover, ADAM17–/– educated macrophages demonstrated a reduced ability to induce cancer cell invasion. Using mass spectrometry–based proteomics and ELISA, we identified heparin-binding EGF (HB-EGF) and amphiregulin, shed by ADAM17 in the cancer cells, as the implicated molecular mediators of macrophage education. Additionally, RNA-Seq and ELISA experiments revealed that ADAM17-dependent HB-EGF ligand release induced the expression and secretion of CXCL chemokines in macrophages, which in turn stimulated cancer cell invasion. In conclusion, we provide evidence that ADAM17 mediates a paracrine EGFR-ligand-chemokine feedback loop, whereby cancer cells hijack macrophages to promote tumor progression.
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- 2022
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4. A prognostic model based on cell-cycle control predicts outcome of breast cancer patients
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Heli Repo, Eliisa Löyttyniemi, Samu Kurki, Lila Kallio, Teijo Kuopio, Kati Talvinen, and Pauliina Kronqvist
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Breast cancer ,Prognosis ,Proliferation ,Cell cycle ,Securin ,Separase ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background A prognostic model combining biomarkers of metaphase-anaphase transition of the cell cycle was developed for invasive breast cancer. The prognostic value and clinical applicability of the model was evaluated in comparison with the routine prognosticators of invasive breast carcinoma. Methods The study comprised 1135 breast cancer patients with complete clinical data and up to 22-year follow-up. Regulators of metaphase-anaphase transition were detected immunohistochemically and the biomarkers with the strongest prognostic impacts were combined into a prognostic model. The prognostic value of the model was tested and evaluated in separate patient materials originating from two Finnish breast cancer centers. Results The designed model comprising immunoexpressions of Securin, Separase and Cdk1 identified 8.4-fold increased risk of breast cancer mortality (p 75%) of patients resulting with favorable as opposed to unfavorable outcome of the model. Along with nodal status, the model showed independent prognostic impact for all breast carcinomas and for subgroups of luminal, N+ and N- disease. Conclusions The impact of the proposed prognostic model in predicting breast cancer survival was comparable to nodal status. However, the model provided additional information in N- breast carcinoma in identifying patients with aggressive course of disease, potentially in need of adjuvant treatments. Concerning N+, in turn, the model could provide evidence for withholding chemotherapy from patients with favorable outcome.
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- 2020
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5. Overexpression of Human Estrogen Biosynthetic Enzyme Hydroxysteroid (17beta) Dehydrogenase Type 1 Induces Adenomyosis-like Phenotype in Transgenic Mice
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Taija Heinosalo, Kalle T. Rytkönen, Niina Saarinen, Päivi Järvensivu, Pauliina Damdimopoulou, Leena Strauss, Satu Orasniemi, Petricia Horshauge, Michael Gabriel, Pasi Koskimies, Claes Ohlsson, Pauliina Kronqvist, and Matti Poutanen
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adenomyosis ,HSD17B1 ,estrogen ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) is an enzyme that converts estrone to estradiol, while adenomyosis is an estrogen-dependent disease with poorly understood pathophysiology. In the present study, we show that mice universally over-expressing human estrogen biosynthetic enzyme HSD17B1 (HSD17B1TG mice) present with adenomyosis phenotype, characterized by histological and molecular evaluation. The first adenomyotic changes with endometrial glands partially or fully infiltrated into the myometrium appeared at the age of 5.5 months in HSD17B1TG females and became more prominent with increasing age. Preceding the phenotype, increased myometrial smooth muscle actin positivity and increased amount of glandular myofibroblast cells were observed in HSD17B1TG uteri. This was accompanied by transcriptomic upregulation of inflammatory and estrogen signaling pathways. Further, the genes upregulated in the HSD17B1TG uterus were enriched with genes previously observed to be induced in the human adenomyotic uterus, including several genes of the NFKB pathway. A 6-week-long HSD17B1 inhibitor treatment reduced the occurrence of the adenomyotic changes by 5-fold, whereas no effect was observed in the vehicle-treated HSD17B1TG mice, suggesting that estrogen is the main upstream regulator of adenomyosis-induced uterine signaling pathways. HSD17B1 is considered as a promising drug target to inhibit estrogen-dependent growth of endometrial disorders. The present data indicate that HSD17B1 over-expression in TG mice results in adenomyotic changes reversed by HSD17B1 inhibitor treatment and HSD17B1 is, thus, a potential novel drug target for adenomyosis.
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- 2022
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6. PTTG1-interacting protein (PTTG1IP/PBF) predicts breast cancer survival
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Heli Repo, Natalia Gurvits, Eliisa Löyttyniemi, Marjukka Nykänen, Minnamaija Lintunen, Henna Karra, Samu Kurki, Teijo Kuopio, Kati Talvinen, Mirva Söderström, and Pauliina Kronqvist
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PTTG1IP ,PBF ,Immunohistochemistry ,Breast cancer ,Prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background PTTG1-interacting protein (PTTG1IP) is an oncogenic protein, which participates in metaphase-anaphase transition of the cell cycle through activation of securin (PTTG1). PTTG1IP promotes the shift of securin from the cell cytoplasm to the nucleus, allowing the interaction between separase and securin. PTTG1IP overexpression has been previously observed in malignant disease, e.g. in breast carcinoma. However, the prognostic value of PTTG1IP in breast carcinoma patients has not previously been revealed. Methods A total of 497 breast carcinoma patients with up to 22-year follow-up were analysed for PTTG1IP and securin immunoexpression. The results were evaluated for correlations with the clinical prognosticators and patient survival. Results In our material, negative PTTG1IP immunoexpression predicted a 1.5-fold risk of breast cancer death (p = 0.02). However, adding securin immunoexpression to the analysis indicated an even stronger and independent prognostic power in the patient material (HR = 2.5, p
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- 2017
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7. L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling
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Guillaume Jacquemet, Habib Baghirov, Maria Georgiadou, Harri Sihto, Emilia Peuhu, Pierre Cettour-Janet, Tao He, Merja Perälä, Pauliina Kronqvist, Heikki Joensuu, and Johanna Ivaska
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Science - Abstract
Filopodia have a prominent role in driving cancer cell invasion. Here, the authors show that L-type calcium channels are a druggable target regulating filopodia stability and maturation into focal adhesions in metastatic breast cancer cells.
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- 2016
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8. Proteomic maps of breast cancer subtypes
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Stefka Tyanova, Reidar Albrechtsen, Pauliina Kronqvist, Juergen Cox, Matthias Mann, and Tamar Geiger
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Science - Abstract
Breast cancers have been extensively studied at the genomic and transcriptomic levels in the hope of tailoring therapeutic regimens. Here the authors generate deep coverage proteomes from several clinical breast cancer samples, and use machine learning techniques to uncover biological processes altered in specific cancer subtypes.
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- 2016
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9. Formin Proteins FHOD1 and INF2 in Triple-Negative Breast Cancer: Association With Basal Markers and Functional Activities
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Vanina D Heuser, Naziha Mansuri, Jasper Mogg, Samu Kurki, Heli Repo, Pauliina Kronqvist, Olli Carpén, and Maria Gardberg
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Basal-like breast cancer is an aggressive form of breast cancer with limited treatment options. The subgroup can be identified immunohistochemically, by lack of hormone receptor expression combined with expression of basal markers such as CK5/6 and/or epidermal growth factor receptor (EGFR). In vitro, several regulators of the actin cytoskeleton are essential for efficient invasion of basal-like breast cancer cell lines. Whether these proteins are expressed in vivo determines the applicability of these findings in clinical settings. The actin-regulating formin protein FHOD1 participates in invasion of the triple-negative breast cancer cell line MDA-MB-231. Here, we measure the expression of FHOD1 protein in clinical triple-negative breast cancers by using immunohistochemistry and further characterize the expression of another formin protein, INF2. We report that basal-like breast cancers frequently overexpress formin proteins FHOD1 and INF2. In cell studies using basal-like breast cancer cell lines, we show that knockdown of FHOD1 or INF2 interferes with very similar processes: maintenance of cell shape, migration, invasion, and proliferation. Inhibition of EGFR, PI3K, or mitogen-activated protein kinase activity does not alter the expression of FHOD1 and INF2 in these cell lines. We conclude that the experimental studies on these formins have implications in the clinical behavior of basal-like breast cancer.
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- 2018
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10. The Reproducibility of Nuclear Morphometric Measurements in Invasive Breast Carcinoma
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Pauliina Kronqvist, Teijo Kuopio, Yrjö Collan, Csaba Horvath, and Ülle Tamm
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
The intraobserver and interobserver reproducibility of computerized nuclear morphometry was determined in repeated measurements of 212 samples of invasive breast cancer. The influence of biological variation and the selection of the measurement area was also tested. Morphometrically determined mean nuclear profile area (Pearson’s r 0.89, grading efficiency (GE) 0.95) and standard deviation (SD) of nuclear profile area (Pearson’s r 0.84, GE 0.89) showed high reproducibility. In this respect, nuclear morphometry equals with other established methods of quantitative pathology and exceeds the results of subjective grading of nuclear atypia in invasive breast cancer. A training period of eight days was sufficient to produce clear improvement in consistency of nuclear morphometry results. By estimating the sources of variation it could be shown that the variation associated with the measurement procedure itself is small. Instead, sample associated variation is responsible for the majority of variation in the measurements (82.9% in mean nuclear profile area and 65.9% in SD of nuclear profile area). This study points out that when standardized methods are applied computerized morphometry is a reproducible and reliable method of assessing nuclear atypia in invasive breast cancer. For further improvement special emphasize should be put on sampling rules of selecting the microscope fields and measurement areas.
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- 1997
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11. Towards an Integrated Online Learning System for Microscopic Pathology: Two Teaching Examples.
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Mikko Kainulainen, Laura Helle, Pauliina Kronqvist, Koen L. Vincken, Friedrich Pawelka, Katarina Korpinen, and Bas A. de Leng
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- 2023
12. Supplementary Figure 4 from ADAM12 Produced by Tumor Cells Rather than Stromal Cells Accelerates Breast Tumor Progression
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Ulla M. Wewer, Arthur M. Mercurio, Atsuko Sehara-Fujisawa, Marie Kveiborg, Pauliina Kronqvist, Reidar Albrechtsen, Camilla Nehammer, and Camilla Fröhlich
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PDF file - 300K, ADAM12 immunolocalization in a subcutanous Lewis Lung tumor. Immunohistochemical staining of ADAM12 in Lewis Lung tumors grown for 15 days in ADAM12+/- mice using A) 2�g/mL affinity purified ADAM12 polyclonal antibody from ProteinTech Group or B) 10 �g/mL normal rabbit IgG fraction (Dako) as primary antibodies. Sections were counterstained with hematoxylin. A and B use identical magnification with scale bar in B = 20�m Detection was performed using the DakoChemMate detection kit (Dako).
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- 2023
13. Supplementary Figure 1 from ADAM12 Produced by Tumor Cells Rather than Stromal Cells Accelerates Breast Tumor Progression
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Ulla M. Wewer, Arthur M. Mercurio, Atsuko Sehara-Fujisawa, Marie Kveiborg, Pauliina Kronqvist, Reidar Albrechtsen, Camilla Nehammer, and Camilla Fröhlich
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PDF file - 213K, A Pan-cytokeratin expression (green) in immortalized PyMT-A12hz and PyMT-A12null tumor cells. Blue represents DAPI staining. Bar = 12 �m. B. Mean (�SD) total tumor burden on FVB/N mice injected subcutaneously in the right flank with PyM-A12hz (n=11) or PyMT-A12null (n=15) tumor cells. *P < 0.05
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- 2023
14. Data from ADAM12 Produced by Tumor Cells Rather than Stromal Cells Accelerates Breast Tumor Progression
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Ulla M. Wewer, Arthur M. Mercurio, Atsuko Sehara-Fujisawa, Marie Kveiborg, Pauliina Kronqvist, Reidar Albrechtsen, Camilla Nehammer, and Camilla Fröhlich
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Expression of ADAM12 is low in most normal tissues but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In this study, we found that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 seems to be dispensable for its tumor-promoting effect. Interestingly, we show that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence tumor progression, but that ADAM12 expression by tumor cells is necessary for tumor progression in these mice. This finding is consistent with our observation that in human breast carcinoma, ADAM12 is almost exclusively located in tumor cells and, only rarely, seen in the tumor-associated stroma. We hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, on the basis of the fact that TGF-β1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-β1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12 synthesis, and growth of these cells in vivo induced more than 200-fold increase in ADAM12 expression. Our observation that ADAM12 expression is significantly higher in the terminal duct lobular units (TDLU) adjacent to human breast carcinoma compared with TDLUs found in normal breast tissue supports our hypothesis that tumor-associated stroma triggers ADAM12 expression. Mol Cancer Res; 9(11); 1449–61. ©2011 AACR.
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- 2023
15. Supplementary Figure 3 from ADAM12 Produced by Tumor Cells Rather than Stromal Cells Accelerates Breast Tumor Progression
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Ulla M. Wewer, Arthur M. Mercurio, Atsuko Sehara-Fujisawa, Marie Kveiborg, Pauliina Kronqvist, Reidar Albrechtsen, Camilla Nehammer, and Camilla Fröhlich
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PDF file - 429K, Whole-mount section used for ADAM12 profiling in TDLUs, ADH, DCIS, and IDC. H&E-stained sections of breast tissue. A, The insert marks a representative example of an area used for the ADAM12 immunostaining presented in Table 1 and Fig. 5. B, TDLUs and ducts co-existing with carcinoma cells. C, An area with ADH. D, An area with DCIS. E, An area with IDC. Scale bar in B = 60 �m, in E = 30 �m. C-E use identical magnification.
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- 2023
16. Supplementary Figure 2 from ADAM12 Produced by Tumor Cells Rather than Stromal Cells Accelerates Breast Tumor Progression
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Ulla M. Wewer, Arthur M. Mercurio, Atsuko Sehara-Fujisawa, Marie Kveiborg, Pauliina Kronqvist, Reidar Albrechtsen, Camilla Nehammer, and Camilla Fröhlich
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PDF file - 238K, Stromal ADAM12 does not influence tumor growthA12null tumor cells examined by Western blot. Western blot analysis of ADAM12 expression in PyMT-A12hz, PyMT-A12null, and B16F10 cell lines. G, Mean (�SD) tumor volumes over time in wild-type (n=5), ADAM12+/- (n=11), or ADAM12-/- (n=6) mice on the C57/Bl6 genetic background injected s.c. with B16F10 melanoma cells.
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- 2023
17. Supplementary table S1 from UBR5 Is Coamplified with MYC in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis
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Jukka Westermarck, Martin Eilers, Ville Hietakangas, Tero Aittokallio, Annika Meinander, Pauliina Kronqvist, Juha Klefström, Joanna W. Pylvänäinen, Laxman Yetukuri, Kati Talvinen, Heidi M. Haikala, Joni Merisaari, Mukund Sharma, Alok Jaiswal, Abhishekh Gupta, Aravind K. Mohan, Maria Llamazares Prada, Ying Liu, and Xi Qiao
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siRNA and primer sequences
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- 2023
18. Supplementary Figures 1-6 from UBR5 Is Coamplified with MYC in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis
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Jukka Westermarck, Martin Eilers, Ville Hietakangas, Tero Aittokallio, Annika Meinander, Pauliina Kronqvist, Juha Klefström, Joanna W. Pylvänäinen, Laxman Yetukuri, Kati Talvinen, Heidi M. Haikala, Joni Merisaari, Mukund Sharma, Alok Jaiswal, Abhishekh Gupta, Aravind K. Mohan, Maria Llamazares Prada, Ying Liu, and Xi Qiao
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Supplementary Figures 1-6. Figure S1: UBR5 and MYC interaction assays and WB controls for RNA-seq. experiment. Fig. S2: MYC and NMYC stability regulation by UBR5 and ubiquitin assays in denaturating conditions. Fig. S3: Additional Drosophila phenotype data. Fig. S4: Colony growth and apoptosis assays in UBR5 depleted control and drug-treated cells. Fig. S5: Role of UBR5 in basal-like breast cancer cells and Kaplan-Meier analyses. Fig. S6: IF and IHC analysis of MYC and UBR5 expression in basal-like TNBC.
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- 2023
19. Data from UBR5 Is Coamplified with MYC in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis
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Jukka Westermarck, Martin Eilers, Ville Hietakangas, Tero Aittokallio, Annika Meinander, Pauliina Kronqvist, Juha Klefström, Joanna W. Pylvänäinen, Laxman Yetukuri, Kati Talvinen, Heidi M. Haikala, Joni Merisaari, Mukund Sharma, Alok Jaiswal, Abhishekh Gupta, Aravind K. Mohan, Maria Llamazares Prada, Ying Liu, and Xi Qiao
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For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (HYD) in Drosophila, HYD suppressed dMYC-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells, UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were coamplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC coamplification. Furthermore, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC-amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis.Significance:These findings identify UBR5 as a novel MYC regulator, the inactivation of which could be very important for understanding of MYC dysregulation on cancer cells.
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- 2023
20. Data from CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis
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Jukka Westermarck, Goutham Narla, Karin de Visser, Emilia Peuhu, Heikki Joensuu, Rene H. Medema, Krister Wennerberg, Jochen Maurer, Laura L. Elo, Pauliina Kronqvist, Denise C. Connolly, Karolina Pavic, Xi Qiao, Harri Sihto, Sofia Khan, Prson Gautam, Tove J. Grönroos, Femke M. Feringa, Julia P. Vainonen, Anna N. Cvrljevic, Umar Butt, Caroline Farrington, Srikar G. Nagelli, and Anni Laine
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Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage–induced initiation of mouse BLBC-like mammary tumors and for survival of HR–defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage–induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage–induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs.Significance:These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage–induced G2–M checkpoint and proliferative signaling.
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- 2023
21. Supplementary Data from CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis
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Jukka Westermarck, Goutham Narla, Karin de Visser, Emilia Peuhu, Heikki Joensuu, Rene H. Medema, Krister Wennerberg, Jochen Maurer, Laura L. Elo, Pauliina Kronqvist, Denise C. Connolly, Karolina Pavic, Xi Qiao, Harri Sihto, Sofia Khan, Prson Gautam, Tove J. Grönroos, Femke M. Feringa, Julia P. Vainonen, Anna N. Cvrljevic, Umar Butt, Caroline Farrington, Srikar G. Nagelli, and Anni Laine
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Supplementary Data from CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis
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- 2023
22. Data from A Role for ADAM12 in Breast Tumor Progression and Stromal Cell Apoptosis
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Ulla M. Wewer, Arthur M. Mercurio, Fritz Rank, Pauliina Kronqvist, Peter Holck, Nikolaj Dietrich, Verena Tischler, Reidar Albrechtsen, Camilla Fröhlich, and Marie Kveiborg
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As in developmental and regenerative processes, cell survival is of fundamental importance in cancer. Thus, a tremendous effort has been devoted to dissecting the molecular mechanisms involved in understanding the resistance of tumor cells to programmed cell death. Recently, the importance of stromal fibroblasts in tumor initiation and progression has been elucidated. Here, we show that stromal cell apoptosis occurs in human breast carcinoma but is only rarely seen in nonmalignant breast lesions. Furthermore, we show that ADAM12, a disintegrin and metalloprotease up-regulated in human breast cancer, accelerates tumor progression in a mouse breast cancer model. ADAM12 does not influence tumor cell proliferation but rather confers both decreased tumor cell apoptosis and increased stromal cell apoptosis. This dual role of ADAM12 in governing cell survival is underscored by the finding that ADAM12 increases the apoptotic sensitivity of nonneoplastic cells in vitro while rendering tumor cells more resistant to apoptosis. Together, these results show that the ability of ADAM12 to influence apoptosis may contribute to tumor progression.
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- 2023
23. Supplementary Figure S1 from A Role for ADAM12 in Breast Tumor Progression and Stromal Cell Apoptosis
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Ulla M. Wewer, Arthur M. Mercurio, Fritz Rank, Pauliina Kronqvist, Peter Holck, Nikolaj Dietrich, Verena Tischler, Reidar Albrechtsen, Camilla Fröhlich, and Marie Kveiborg
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Supplementary Figure S1 from A Role for ADAM12 in Breast Tumor Progression and Stromal Cell Apoptosis
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- 2023
24. CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis
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Sofia Khan, Goutham Narla, Tove J. Grönroos, Harri Sihto, Umar Butt, Jochen Maurer, Jukka Westermarck, René H. Medema, Anna Cvrljevic, Julia P. Vainonen, Denise C. Connolly, Xi Qiao, Karolina Pavic, Anni Laine, Krister Wennerberg, Femke M. Feringa, Karin E. de Visser, Pauliina Kronqvist, Srikar G. Nagelli, Caroline Farrington, Laura L. Elo, Prson Gautam, Heikki Joensuu, Emilia Peuhu, Computational Systems Medicine, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, Department of Pathology, Helsinki University Hospital Area, Krister Wennerberg / Principal Investigator, Research Programs Unit, Heikki Joensuu / Principal Investigator, Clinicum, HUS Comprehensive Cancer Center, Department of Oncology, Functional Genomics, and Amsterdam Neuroscience - Neurodegeneration
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Cancer Research ,Proteome ,Carcinogenesis ,RAD51 ,Tumor initiation ,medicine.disease_cause ,Autoantigens ,ACTIVATION ,Mice ,0302 clinical medicine ,E2F1 ,Triple-negative breast cancer ,Mice, Knockout ,Recombination, Genetic ,0303 health sciences ,Cell Cycle ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,Immunohistochemistry ,3. Good health ,Chromatin ,DNA-Binding Proteins ,Oncology ,030220 oncology & carcinogenesis ,Female ,SENSITIVITY ,Signal Transduction ,9,10-Dimethyl-1,2-benzanthracene ,3122 Cancers ,Mitosis ,Breast Neoplasms ,Mice, Transgenic ,Biology ,Article ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Cell Line, Tumor ,REVEALS ,medicine ,C-MYC ,Animals ,Humans ,YEAST ,Cell Proliferation ,030304 developmental biology ,P53 ,Membrane Proteins ,BRCA1 ,GENE ,HOMOLOG ,Mutation ,Cancer research ,Carrier Proteins ,Homologous recombination ,DNA Damage - Abstract
Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage–induced initiation of mouse BLBC-like mammary tumors and for survival of HR–defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage–induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage–induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage–induced G2–M checkpoint and proliferative signaling.
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- 2021
25. Varying outcomes of triple-negative breast cancer in different age groups - prognostic value of clinical features and proliferation
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Hilda Vihervuori, Katarina Korpinen, Tuomo-Artturi Autere, Heli Repo, Kati Talvinen, and Pauliina Kronqvist
- Abstract
Purpose: Triple-negative breast cancer (TNBC) is an aggressive disease lacking specific biomarkers to guide treatment decisions. We evaluated the combined prognostic impact of clinical features and novel biomarkers of cell cycle-progression in age-dependent subgroups of TNBC patients. Methods: 147 TNBC patients with complete clinical data and up to 18-year follow-up were collected from Turku University Hospital, Finland. Eight biomarkers for cell division were immunohistochemically detected to evaluate their clinical applicability in relation to patient and tumor characteristics. Results: Age at diagnosis was the decisive factor predicting disease-specific mortality in TNBC (p = 0.002). The established prognostic features, nodal status and Ki-67, predicted survival only when combined with age. The outcome and prognostic features differed significantly between age groups, middle-aged patients showing the most favorable outcome. Among young patients, only lack of basal differentiation predicted disease outcome, indicating 4.5-fold mortality risk (p=0.03). Among patients aged >57, the established prognostic features predicted disease outcome with up to 3.0-fold mortality risk for tumor size ≥2cm (p=0.001). Concerning cell proliferation, Ki-67 alone was a significant prognosticator among patients aged > 57 years (p=0.009). Among the studied cell cycle-specific biomarkers, only geminin predicted disease outcome, indicating up to 6.2-fold increased risk of mortality for tumor size Conclusions: Traditional clinical features do not provide optimal prognostic characterization for all TNBC patients. Young age should be considered as an additional adverse prognostic feature in therapeutic considerations. Increased proliferation, as evaluated using Ki-67 or geminin immunohistochemistry, showed potential in detecting survival differences in subgroups of TNBC.
- Published
- 2022
26. Overexpression of Human Estrogen Biosynthetic Enzyme Hydroxysteroid (17beta) Dehydrogenase Type 1 Induces Adenomyosis-like Phenotype in Transgenic Mice
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Poutanen, Taija Heinosalo, Kalle T. Rytkönen, Niina Saarinen, Päivi Järvensivu, Pauliina Damdimopoulou, Leena Strauss, Satu Orasniemi, Petricia Horshauge, Michael Gabriel, Pasi Koskimies, Claes Ohlsson, Pauliina Kronqvist, and Matti
- Subjects
adenomyosis ,HSD17B1 ,estrogen - Abstract
Hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) is an enzyme that converts estrone to estradiol, while adenomyosis is an estrogen-dependent disease with poorly understood pathophysiology. In the present study, we show that mice universally over-expressing human estrogen biosynthetic enzyme HSD17B1 (HSD17B1TG mice) present with adenomyosis phenotype, characterized by histological and molecular evaluation. The first adenomyotic changes with endometrial glands partially or fully infiltrated into the myometrium appeared at the age of 5.5 months in HSD17B1TG females and became more prominent with increasing age. Preceding the phenotype, increased myometrial smooth muscle actin positivity and increased amount of glandular myofibroblast cells were observed in HSD17B1TG uteri. This was accompanied by transcriptomic upregulation of inflammatory and estrogen signaling pathways. Further, the genes upregulated in the HSD17B1TG uterus were enriched with genes previously observed to be induced in the human adenomyotic uterus, including several genes of the NFKB pathway. A 6-week-long HSD17B1 inhibitor treatment reduced the occurrence of the adenomyotic changes by 5-fold, whereas no effect was observed in the vehicle-treated HSD17B1TG mice, suggesting that estrogen is the main upstream regulator of adenomyosis-induced uterine signaling pathways. HSD17B1 is considered as a promising drug target to inhibit estrogen-dependent growth of endometrial disorders. The present data indicate that HSD17B1 over-expression in TG mice results in adenomyotic changes reversed by HSD17B1 inhibitor treatment and HSD17B1 is, thus, a potential novel drug target for adenomyosis.
- Published
- 2022
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27. Interactive visual tools as triggers of collaborative reasoning in entry-level pathology.
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Markus Nivala, Hans Rystedt, Roger Säljö, Pauliina Kronqvist, and Erno Lehtinen
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- 2012
- Full Text
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28. UBR5 Is Coamplified with MYC in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis
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Juha Klefström, Joanna W Pylvänäinen, Tero Aittokallio, Martin Eilers, Ying Liu, Pauliina Kronqvist, Ville Hietakangas, Mukund Sharma, Laxman Yetukuri, Abhishekh Gupta, Jukka Westermarck, Alok Jaiswal, Xi Qiao, Heidi M. Haikala, Annika Meinander, Joni Merisaari, Aravind K. Mohan, Kati Talvinen, and Maria Llamazares Prada
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0301 basic medicine ,Regulation of gene expression ,Cancer Research ,biology ,Chemistry ,Ubiquitin ligase ,law.invention ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,law ,Apoptosis ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Suppressor ,Gene silencing ,Phosphorylation - Abstract
For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (HYD) in Drosophila, HYD suppressed dMYC-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells, UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were coamplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC coamplification. Furthermore, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC-amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis. Significance: These findings identify UBR5 as a novel MYC regulator, the inactivation of which could be very important for understanding of MYC dysregulation on cancer cells.
- Published
- 2020
29. Tumor margins that lead to reoperation in breast cancer: A retrospective register study of 4,489 patients
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Maiju, Lepomäki, Ulla, Karhunen-Enckell, Jalmari, Tuominen, Pauliina, Kronqvist, Niku, Oksala, Teemu, Murtola, and Antti, Roine
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Adult ,Aged, 80 and over ,Reoperation ,Carcinoma, Ductal, Breast ,Margins of Excision ,Breast Neoplasms ,Middle Aged ,Prognosis ,Carcinoma, Lobular ,Carcinoma, Intraductal, Noninfiltrating ,Humans ,Female ,Mastectomy ,Aged ,Follow-Up Studies ,Retrospective Studies - Abstract
Optimal margins for ductal carcinoma in situ (DCIS) remain controversial in breast-conserving surgery (BCS) and mastectomy. We examine the association of positive margins, reoperations, DCIS and age.A retrospective study of histopathological reports (4489 patients). Margin positivity was defined as ink on tumor for invasive carcinoma. For DCIS, we applied 2 mm anterior and side margin thresholds, and ink on tumor in the posterior margin.The incidence of positive side margins was 20% in BCS and 5% in mastectomies (p 0.001). Of these patients, 68% and 14% underwent a reoperation (p 0.001). After a positive side margin in BCS, the reoperation rates according to age groups were 74% (49), 69% (50-64), 68% (65-79), and 42% (80+) (p = 0.013). Of BCS patients with invasive carcinoma in the side margin, 73% were reoperated on. A reoperation was performed in 70% of patients with a close (≤1 mm) DCIS side margin, compared to 43% with a wider (1.1-2 mm) margin (p = 0.002). The reoperation rates were 55% in invasive carcinoma with close DCIS, 66% in close extensive intraductal component (EIC), and 83% in close pure DCIS (p 0.001).Individual assessment as opposed to rigid adherence to guidelines was used in the decision on reoperation.
- Published
- 2021
30. Publisher Correction: Cargo-specific recruitment in clathrin- and dynamin-independent endocytosis
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Paulina Moreno-Layseca, Niklas Z. Jäntti, Rashmi Godbole, Christian Sommer, Guillaume Jacquemet, Hussein Al-Akhrass, James R. W. Conway, Pauliina Kronqvist, Roosa E. Kallionpää, Leticia Oliveira-Ferrer, Pasquale Cervero, Stefan Linder, Martin Aepfelbacher, Henrik Zauber, James Rae, Robert G. Parton, Andrea Disanza, Giorgio Scita, Satyajit Mayor, Matthias Selbach, Stefan Veltel, and Johanna Ivaska
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Cell Biology - Published
- 2022
31. Tumor-infiltrating lymphocytes and CD8+ T cells predict survival of triple-negative breast cancer
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Kati Talvinen, H. Vihervuori, L. Kallio, Samu Kurki, Minnamaija Lintunen, T. A. Autere, Heli Repo, and Pauliina Kronqvist
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Stromal cell ,Tissue microarray ,business.industry ,Tumor-infiltrating lymphocytes ,General Medicine ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Immunohistochemistry ,Cytotoxic T cell ,business ,Triple-negative breast cancer ,CD8 - Abstract
Purpose Tumor inflammatory response was evaluated as a prognostic feature in triple-negative breast cancer (TNBC) and compared with the clinical prognosticators of breast cancer and selected biomarkers of cancer cell proliferation. Methods TNBC patients (n = 179) with complete clinical data and up to 18-year follow-up were obtained from Auria biobank, Turku University Hospital, Turku, Finland. Tumor-infiltrating lymphocytes (TILs) and several subtypes of inflammatory cells detected with immunohistochemistry were evaluated in different tumor compartments in full tissue sections and tissue microarrays. Results Deficiency of stromal TILs and low number of CD8+ T cells independently predicted mortality in TNBC (HR 2.4, p 0.02 and HR 2.1, p 0.02, respectively). Each 10% decrease in stromal TILs resulted in 20% increased risk of mortality. An average of 13.2-year survival difference was observed between the majority (> 75%) of patients with low (+ T cells. The prognostic value of TILs and CD8+ T cells varied when evaluated in different tumor compartments. TILs and CD8+ T cells were significantly associated with Securin and Separase, essential regulators of metaphase–anaphase transition of the cell cycle. Discussion TILs and CD8+ T cells provide additional prognostic value to the established clinical prognostic markers in TNBC. However, possible clinical applications would still benefit from systematic guidelines for evaluating tumor inflammatory response. Increasing understanding on the interactions between the regulation of cancer cell proliferation and inflammatory response may in future advance treatment of TNBC.
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- 2019
32. Stromal Interaction Molecule 1 (STIM1) Knock-down Attenuates Migration and Proliferation and Enhances the Expression of Thyroid Specific Proteins in Human Follicular Thyroid Cancer Cells
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Muhammad Yasir Asghar, Taru Lassila, Ilkka Paatero, Van Dien Nguyen, Pauliina Kronqvist, Jixi Zhang, Anna Slita, Christoffer Löf, You Zhou, Jessica Rosenholm, and Kid Törnquist
- Subjects
inorganic chemicals - Abstract
Stromal interaction molecule 1 (STIM1) and the ORAI1 calcium channel mediate store-operated calcium entry (SOCE) and regulate a multitude of cellular functions. The identity and function of these proteins in thyroid cancer remained elusive. We show that STIM1 and ORAI1 expression is elevated in thyroid cancer cell lines, compared with primary thyroid cells. Knock-down of STIM1 or ORAI1 attenuated SOCE, reduced migration, and expression of promigratory sphingosine 1-phosphate (S1P) and vascular endothelial growth factor-2 (VEGFR2) receptors in thyroid cancer ML-1 cells. Cell proliferation was attenuated in these knock-down cells due to increased G1 phase of the cell cycle and enhanced expression of cyclin-dependent kinase inhibitory proteins p21 and p27. STIM1 protein was upregulated in thyroid cancer tissue, compared with normal tissue. Downregulation of STIM1 restored expression of thyroid stimulating hormone receptor (TSHR), thyroid specific proteins and increased iodine uptake. STIM1 knockdown ML-1 cells were more susceptible to chemotherapeutic drugs, and significantly reduced tumor growth in Zebrafish. Furthermore, STIM1-siRNA-loaded mesoporous polydopamine nanoparticles attenuated migration and proliferation of ML-1 cells. Taken together, our data suggest that STIM1 is a potential diagnostic and therapeutic target for treatment of thyroid cancer.
- Published
- 2021
33. Stromal interaction molecule 1 (STIM1) knock down attenuates invasion and proliferation and enhances the expression of thyroid-specific proteins in human follicular thyroid cancer cells
- Author
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Pauliina Kronqvist, Christoffer Löf, You Zhou, Ilkka Paatero, Jessica M. Rosenholm, Taru Lassila, Van Dien Nguyen, Jixi Zhang, Kid Törnquist, Anna Slita, Muhammad Yasir Asghar, and Medicum
- Subjects
Male ,Indoles ,ORAI1 Protein ,Polymers ,Proliferation ,Thyroid Gland ,Metastasis ,0302 clinical medicine ,Invasion ,RNA, Small Interfering ,Receptor ,Thyroid cancer ,Zebrafish ,Migration ,Aged, 80 and over ,0303 health sciences ,Chemistry ,Thyroid ,Cell cycle ,Middle Aged ,3. Good health ,Neoplasm Proteins ,Up-Regulation ,ORAI1 ,Stromal interaction molecule 1 (STIM1) ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,ORAI1 calcium channel ,Molecular Medicine ,Female ,Original Article ,inorganic chemicals ,Adult ,Adolescent ,CALCIUM ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,DELIVERY ,Young Adult ,Downregulation and upregulation ,SPHINGOSINE 1-PHOSPHATE ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Calcium Signaling ,Stromal Interaction Molecule 1 ,Thyroid Neoplasms ,Follicular thyroid cancer ,Molecular Biology ,030304 developmental biology ,Aged ,Cell Proliferation ,Pharmacology ,HALLMARKS ,CHANNELS ,Cell growth ,G1 Phase ,PATHWAYS ,Cell Biology ,Store-operated calcium entry (SOCE) ,medicine.disease ,Thyroid Epithelial Cells ,METASTASIS ,Cancer research ,1182 Biochemistry, cell and molecular biology ,Nanoparticles ,Calcium Channels - Abstract
Stromal interaction molecule 1 (STIM1) and the ORAI1 calcium channel mediate store-operated calcium entry (SOCE) and regulate a multitude of cellular functions. The identity and function of these proteins in thyroid cancer remain elusive. We show that STIM1 and ORAI1 expression is elevated in thyroid cancer cell lines, compared to primary thyroid cells. Knock-down of STIM1 or ORAI1 attenuated SOCE, reduced invasion, and the expression of promigratory sphingosine 1-phosphate and vascular endothelial growth factor-2 receptors in thyroid cancer ML-1 cells. Cell proliferation was attenuated in these knock-down cells due to increased G1 phase of the cell cycle and enhanced expression of cyclin-dependent kinase inhibitory proteins p21 and p27. STIM1 protein was upregulated in thyroid cancer tissue, compared to normal tissue. Downregulation of STIM1 restored expression of thyroid stimulating hormone receptor, thyroid specific proteins and increased iodine uptake. STIM1 knockdown ML-1 cells were more susceptible to chemotherapeutic drugs, and significantly reduced tumor growth in Zebrafish. Furthermore, STIM1-siRNA-loaded mesoporous polydopamine nanoparticles attenuated invasion and proliferation of ML-1 cells. Taken together, our data suggest that STIM1 is a potential diagnostic and therapeutic target for treatment of thyroid cancer. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-021-03880-0.
- Published
- 2021
34. Cargo-specific recruitment in clathrin and dynamin-independent endocytosis
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Christian Sommer, Roosa E. Kallionpää, Satyajit Mayor, Stefan Linder, Stefan Veltel, Guillaume Jacquemet, Pauliina Kronqvist, Johanna Ivaska, Pasquale Cervero, Paulina Moreno-Layseca, James Rae, Martin Aepfelbacher, Niklas Z. Jäntti, Giorgio Scita, Hussein Al-Akhrass, Robert G. Parton, Andrea Disanza, Matthias Selbach, Rashmi Godbole, and Leticia Oliveira-Ferrer
- Subjects
biology ,Chemistry ,media_common.quotation_subject ,Endocytic cycle ,Integrin ,Endocytosis ,Clathrin ,Cell biology ,biology.protein ,Internalization ,Actin ,Tissue homeostasis ,Dynamin ,media_common - Abstract
Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis, and cancer invasion and is often hijacked by viral infections 1. Unlike clathrin-mediated endocytosis, which exploits cargo-specific adaptors for selective protein internalization, the clathrin and dynamin-independent endocytic pathway (CLIC-GEEC, CG-pathway) has until now been considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids 2,3. Although the core molecular players of CG endocytosis have been recently defined, no cargo-specific adaptors are known and evidence of selective protein uptake into the pathway is lacking 3. Here, we identify the first cargo-specific adaptor for CG-endocytosis and demonstrate its clinical relevance in breast cancer progression. By combining unbiased molecular characterization and super-resolution imaging, we identified the actin-binding protein swiprosin-1 (EFHD2) as a cargo-specific adaptor regulating integrin internalization via the CG-pathway. Swiprosin-1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery, IRSp53 and actin. Swiprosin-1 is critical for integrin endocytosis, but not for other CG-cargo and supports integrin-dependent cancer cell migration and invasion, with clinically relevant implications for breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG-pathway and opens the possibility to discover more adaptors regulating it.
- Published
- 2020
35. Cargo-specific recruitment in clathrin- and dynamin-independent endocytosis
- Author
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Paulina, Moreno-Layseca, Niklas Z, Jäntti, Rashmi, Godbole, Christian, Sommer, Guillaume, Jacquemet, Hussein, Al-Akhrass, James R W, Conway, Pauliina, Kronqvist, Roosa E, Kallionpää, Leticia, Oliveira-Ferrer, Pasquale, Cervero, Stefan, Linder, Martin, Aepfelbacher, Henrik, Zauber, James, Rae, Robert G, Parton, Andrea, Disanza, Giorgio, Scita, Satyajit, Mayor, Matthias, Selbach, Stefan, Veltel, and Johanna, Ivaska
- Subjects
Dynamins ,Cell Movement ,rab GTP-Binding Proteins ,Integrin beta1 ,Intracellular Signaling Peptides and Proteins ,Humans ,Biological Transport ,Breast Neoplasms ,Female ,Actins ,Clathrin ,Endocytosis - Abstract
Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis and cancer invasion. Unlike cargo-specific clathrin-mediated endocytosis, the clathrin- and dynamin-independent endocytic pathway (CLIC-GEEC, CG pathway) is considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. While the core molecular players of CG-endocytosis have been recently defined, evidence of cargo-specific adaptors or selective uptake of proteins for the pathway are lacking. Here we identify the actin-binding protein Swiprosin-1 (Swip1, EFHD2) as a cargo-specific adaptor for CG-endocytosis. Swip1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery-Arf1, IRSp53 and actin-and is critical for integrin endocytosis. Through this function, Swip1 supports integrin-dependent cancer-cell migration and invasion, and is a negative prognostic marker in breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG pathway and a role for specific adaptors in recruitment into this endocytic route.
- Published
- 2020
36. CIP2A interacts with TopBP1 and is selectively essential for DNA damage-induced basal-like breast cancer tumorigenesis
- Author
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Jochen Maurer, Denise C. Connolly, Prson Gautam, Jukka Westermarck, Karolina Pavic, Caroline Farrington, Umar Butt, René H. Medema, Anna Cvrljevic, Femke M. Feringa, Pauliina Kronqvist, Heikki Joensuu, Sofia Khan, Emilia Peuhu, Goutham Narla, Karin E. de Visser, Srikar G. Nagelli, Laura L. Elo, Xi Qiao, Tove J. Grönroos, Harri Sihto, Krister Wennerberg, Anni Laine, and Julia P. Vainonen
- Subjects
0303 health sciences ,DNA damage ,Chromatin binding ,RAD51 ,Cancer ,Biology ,medicine.disease ,medicine.disease_cause ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,PARP1 ,Breast cancer ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,E2F1 ,Carcinogenesis ,030304 developmental biology - Abstract
Despite saturated genetic profiling of breast cancers, oncogenic drivers for the clinically challenging basal-like breast cancer (BLBC) subtype are still poorly understood. Here, we demonstrate that CIP2A is selectively essential for DNA damage-induced initiation of mouse BLBC tumors, but not of other cancer types. Mechanistically, CIP2A was discovered genome-widely the closest functional homologue for DNA-damage proteins TopBP1, RHNO, POLQ, NBN and PARP1. CIP2A directly interacts with the ATR-activation domain of TopBP1, and dampens both, chromatin binding of TopBP1 and RAD51, and G2/M checkpoint in DNA-damaged cells. CIP2A also drives BLBC-associated proliferative MYC and E2F1 signaling. Consistently with high DNA-damage response activity BLBCs, and CIP2A’s novel role in checkpoint signaling, CIP2A was found essential for DNA-damaged, and BRCA-mutant BLBC cells. Selective role for CIP2A as BLBC driver was supported by association of high CIP2A expression with poor patient prognosis only in BLBC, but not in other breast cancer types. Therapeutically, small molecule reactivators of PP2A (SMAPs) phenocopy CIP2A-dependent DNA damage response, and inhibit in vivo growth of patient-derived BLBC xenograft. In summary, we discover sub-type selective essential role for CIP2A in BLBC initiation and maintenance that can be explained by its newly discovered association with DNA-damage response, coordinated with regulation of proliferative signaling. The results also identify therapeutic strategy for CIP2A-dependent BLBCs.
- Published
- 2020
37. A prognostic model based on cell-cycle control predicts outcome of breast cancer patients
- Author
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Teijo Kuopio, Heli Repo, Lila Kallio, Samu Kurki, Kati Talvinen, Pauliina Kronqvist, and Eliisa Löyttyniemi
- Subjects
Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Proliferation ,Breast Neoplasms ,Cell Cycle Proteins ,Disease ,Kaplan-Meier Estimate ,Cell cycle ,lcsh:RC254-282 ,Breast cancer ,Surgical oncology ,Internal medicine ,Genetics ,medicine ,Biomarkers, Tumor ,Humans ,Breast ,Separase ,Mastectomy ,Metaphase ,Aged ,Aged, 80 and over ,Chemotherapy ,Models, Statistical ,business.industry ,Carcinoma, Ductal, Breast ,Cell Cycle Checkpoints ,Chemoradiotherapy, Adjuvant ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,Immunohistochemistry ,Securin ,Prognostic model ,Breast carcinoma ,business ,Anaphase ,Research Article ,Follow-Up Studies - Abstract
Background A prognostic model combining biomarkers of metaphase-anaphase transition of the cell cycle was developed for invasive breast cancer. The prognostic value and clinical applicability of the model was evaluated in comparison with the routine prognosticators of invasive breast carcinoma. Methods The study comprised 1135 breast cancer patients with complete clinical data and up to 22-year follow-up. Regulators of metaphase-anaphase transition were detected immunohistochemically and the biomarkers with the strongest prognostic impacts were combined into a prognostic model. The prognostic value of the model was tested and evaluated in separate patient materials originating from two Finnish breast cancer centers. Results The designed model comprising immunoexpressions of Securin, Separase and Cdk1 identified 8.4-fold increased risk of breast cancer mortality (p 75%) of patients resulting with favorable as opposed to unfavorable outcome of the model. Along with nodal status, the model showed independent prognostic impact for all breast carcinomas and for subgroups of luminal, N+ and N- disease. Conclusions The impact of the proposed prognostic model in predicting breast cancer survival was comparable to nodal status. However, the model provided additional information in N- breast carcinoma in identifying patients with aggressive course of disease, potentially in need of adjuvant treatments. Concerning N+, in turn, the model could provide evidence for withholding chemotherapy from patients with favorable outcome.
- Published
- 2020
38. HSD17B1 expression induces inflammation-aided rupture of mammary gland myoepithelium
- Author
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Pauliina Kronqvist, Janne Hakkarainen, Niina Saarinen, Taija Heinosalo, Päivi Järvensivu, and Matti Poutanen
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,17-Hydroxysteroid Dehydrogenases ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Mammary gland ,Mammary Gland Tissue ,Estrogen receptor ,Mice, Transgenic ,Estrone ,Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Mammary Glands, Animal ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Animals ,Inflammation ,Myoepithelial cell ,Epithelial Cells ,Prolactin ,030104 developmental biology ,medicine.anatomical_structure ,Receptors, Estrogen ,Oncology ,chemistry ,Mammary Epithelium ,Estrogen ,030220 oncology & carcinogenesis ,Female ,HSD17B1 ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
Hydroxysteroid (17-beta) dehydrogenase type 1 (HSD17B1) converts low-active estrogen estrone to highly active estradiol. Estradiol is necessary for normal postpubertal mammary gland development; however, elevated estradiol levels increase mammary tumorigenesis. To investigate the significance of the human HSD17B1 enzyme in the mammary gland, transgenic mice universally overexpressing human HSD17B1 were used (HSD17B1TG mice). Mammary glands obtained from HSD17B1TG females at different ages were investigated for morphology and histology, and HSD17B1 activity and estrogen receptor activation in mammary gland tissue were assessed. To study the significance of HSD17B1 enzyme expression locally in mammary gland tissue, HSD17B1-expressing mammary epithelium was transplanted into cleared mammary fat pads of wild-type females, and the effects on mammary gland estradiol production, epithelial cells and the myoepithelium were investigated. HSD17B1TG females showed increased estrone to estradiol conversion and estrogen-response element-driven estrogen receptor signaling in mammary gland tissue, and they showed extensive lobuloalveolar development that was further enhanced by age along with an increase in serum prolactin concentrations. At old age, HSD17B1TG females developed mammary cancers. Mammary-restricted HSD17B1 expression induced lesions at the sites of ducts and alveoli, accompanied by peri- and intraductal inflammation and disruption of the myoepithelial cell layer. The lesions were shown to be estrogen dependent, as treatment with an antiestrogen, ICI 182,780, starting when lesions were already established reversed the phenotype. These data elucidate the ability of human HSD17B1 to enhance estrogen action in the mammary glandin vivoand indicate that HSD17B1 is a factor inducing phenotypic alterations associated with mammary tumorigenesis.
- Published
- 2018
39. Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity
- Author
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Dagmara Kaczynska, Karl Deisseroth, Carlos Fernández Moro, Przemysław Mitura, Loránd L. Kis, Sara Corvigno, Ayako Miyakawa, Kazuhiro Matsumoto, Shigeaki Kanatani, Pauliina Kronqvist, Carina Strell, Lauri Louhivuori, Mototsugu Oya, Nobuyuki Tanaka, Arne Östman, Claes Lindh, Joseph W. Carlson, Patrick Micke, Andrzej Stepulak, Cecilia Sahlgren, Raju Tomer, Per Uhlén, Peter Wiklund, Artur Mezheyeuski, Hanna Dahlstrand, Johan Hartman, and Soft Tissue Biomech. & Tissue Eng.
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,Tumour heterogeneity ,Genetic heterogeneity ,Angiogenesis ,Biomedical Engineering ,Medicine (miscellaneous) ,Cancer ,Bioengineering ,Biology ,SDG 3 – Goede gezondheid en welzijn ,medicine.disease ,Computer Science Applications ,03 medical and health sciences ,030104 developmental biology ,SDG 3 - Good Health and Well-being ,Biopsy ,Cancer cell ,medicine ,Epigenetics ,Biotechnology ,Tissue biopsy - Abstract
Intratumoral heterogeneity is a critical factor when diagnosing and treating patients with cancer. Marked differences in the genetic and epigenetic backgrounds of cancer cells have been revealed by advances in genome sequencing, yet little is known about the phenotypic landscape and the spatial distribution of intratumoral heterogeneity within solid tumours. Here, we show that three-dimensional light-sheet microscopy of cleared solid tumours can identify unique patterns of phenotypic heterogeneity, in the epithelial-to-mesenchymal transition and in angiogenesis, at single-cell resolution in whole formalin-fixed paraffin-embedded (FFPE) biopsy samples. We also show that cleared FFPE samples can be re-embedded in paraffin after examination for future use, and that our tumour-phenotyping pipeline can determine tumour stage and stratify patient prognosis from clinical samples with higher accuracy than current diagnostic methods, thus facilitating the design of more efficient cancer therapies. A method that identifies patterns of tumour heterogeneity in intact biopsy samples using 3D light-sheet microscopy stratifies patients by tumour stage.
- Published
- 2017
40. Separase is a marker for prognosis and mitotic activity in breast cancer
- Author
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Marjukka Nykänen, Teijo Kuopio, Pauliina Kronqvist, Eliisa Löyttyniemi, Kati Talvinen, and Natalia Gurvits
- Subjects
0301 basic medicine ,entsyymit ,Cancer Research ,cyclin B1 ,proliferation ,enzymes ,Mitosis ,markers ,Breast Neoplasms ,Biology ,ta3111 ,03 medical and health sciences ,breast cancer ,Breast cancer ,separase ,Biomarkers, Tumor ,medicine ,Humans ,Proliferation Marker ,Cyclin B1 ,Molecular Diagnostics ,Survival rate ,Neoplasm Staging ,Anaphase ,Genetics ,rintasyöpä ,securin ,Prognosis ,ta3122 ,medicine.disease ,Survival Rate ,030104 developmental biology ,Oncology ,Securin ,markkerit ,Cancer research ,Female ,Separase ,Breast carcinoma ,ESPL1 - Abstract
Background: Cancer cell proliferation is a critical feature in classifying and predicting the outcome of breast carcinoma. Separase has a central role in cell cycle progression in unleashing sister-chromatids at anaphase onset. Abnormally functioning separase is known to lead to chromosomal instability. Methods: The study comprises 349 breast carcinoma patients treated in Central Hospital of Central Finland. The prognostic value, role as a proliferation marker and regulatory interactions of separase are evaluated by immunohistochemical and double- and triple-immunofluorescence (IF) detections based on complete clinical data and >22-year follow-up of the patient material. Results: In our material, abnormal separase expression predicted doubled risk of breast cancer death (P
- Published
- 2017
41. PLA2G7associates with hormone receptor negativity in clinical breast cancer samples and regulates epithelial-mesenchymal transition in cultured breast cancer cells
- Author
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Paula Vainio, Anne Kallioniemi, Pauliina Kronqvist, Klaus Pantel, Olli Carpén, Olli Kallioniemi, Laura Lehtinen, Volkmar Mueller, Heini Huhtala, Harriet Wikman, and Kristiina Iljin
- Subjects
0301 basic medicine ,CA15-3 ,Oncology ,medicine.medical_specialty ,biology ,business.industry ,CA 15-3 ,Cancer ,Vimentin ,medicine.disease ,3. Good health ,Pathology and Forensic Medicine ,Metastasis ,03 medical and health sciences ,Prostate cancer ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,biology.protein ,Epithelial–mesenchymal transition ,skin and connective tissue diseases ,business - Abstract
Breast cancer is the leading cause of cancer-related deaths in women due to distinct cancer subtypes associated with early recurrence and aggressive metastatic progression. High lipoprotein-associated phospholipase A2 (PLA2G7) expression has previously been associated with aggressive disease and metastasis in prostate cancer. Here, we explore the expression pattern and functional role of PLA2G7 in breast cancer. First, a bioinformatic analysis of genome-wide gene expression data from 970 breast samples was carried out to evaluate the expression pattern of PLA2G7 mRNA in breast cancer. Second, the expression profile of PLA2G7 was studied in 1042 breast cancer samples including 89 matched lymph node metastasis samples using immunohistochemistry. Third, the effect of PLA2G7 silencing on genome-wide gene expression profile was studied and validated in cultured breast cancer cells expressing PLA2G7 at high level. Last, the expression pattern of PLA2G7 mRNA was investigated in 24 nonmalignant tissue samples and 65 primary and 7 metastatic tumour samples derived from various organs using qRT-PCR. The results from clinical breast cancer samples indicated that PLA2G7 is overexpressed in a subset of breast cancer samples compared to its expression in benign breast tissue samples and that high PLA2G7 expression associated with hormone receptor negativity as well as with poor prognosis in a subset of breast cancer samples. In vitro functional studies highlighted the putative role of PLA2G7 in the regulation of epithelial-mesenchymal transition (EMT)-related signalling pathways, vimentin and E-cadherin protein expression as well as cell migration in cultured breast cancer cells. Furthermore, supporting the findings in breast and prostate cancer, high PLA2G7 mRNA expression was associated with metastatic cancer in four additional organs of origin. In conclusion, our results indicate that PLA2G7 is highly expressed in a subset of metastatic and aggressive breast cancers and in metastatic samples of various tissues of origin and promotes EMT and migration in cultured breast cancer cells.
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- 2017
42. Control of MYC-dependent apoptotic threshold by a co-amplified ubiquitin E3 ligase UBR5
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Ying Liu, Abhishekh Gupta, Pauliina Kronqvist, Ville Hietakangas, Kati Talvinen, Joanna W Pylvänäinen, Alok Jaiswal, Juha Klefström, Heidi M. Haikala, Maria Llamazares Prada, Tero Aittokallio, Martin Eilers, Mukund Sharma, Jukka Westermarck, Xi Qiao, Annika Meinander, and Laxman Yetukuri
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0303 health sciences ,biology ,Chemistry ,Cell growth ,Cancer ,medicine.disease ,3. Good health ,Ubiquitin ligase ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,Cell killing ,Ubiquitin ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,medicine ,Degron ,030304 developmental biology - Abstract
MYC protein expression has to be tightly controlled to allow for maximal cell proliferation without inducing apoptosis. Here we discover UBR5 as a novel MYC ubiquitin ligase and demonstrate how it functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 effects on MYC protein stability are independent on N-terminal FBW7 degron of MYC. Endogenous UBR5 inhibition induces MYC protein expression and activates MYC target genes. Moreover, UBR5 governs MYC-dependent phenotypes in vivo in Drosophila. In cancer cells, UBR5-mediated MYC protein suppression diminishes cell killing activity of cancer therapeutics. Further, we demonstrate that UBR5 dominates MYC protein expression at the single-cell level in human basal-type breast cancer tissue. Myc and Ubr5 are co-amplified in MYC-driven human cancer types, and UBR5 controls MYC-mediated apoptotic threshold in co-amplified basal type breast cancer cells. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC protein expression in vivo. Clinically, expression of UBR5 may be important for protection of breast cancer cells from drug-induced, and MYC-dependent, apoptosis.
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- 2019
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43. Prognostic implications of securin expression and sub-cellular localization in human breast cancer
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Teijo Kuopio, Eliisa Löyttyniemi, J Anttinen, Kati Talvinen, Pauliina Kronqvist, Heli Repo, Natalia Gurvits, and Marjukka Nykänen
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Adult ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Fluorescent Antibody Technique ,Breast Neoplasms ,Kaplan-Meier Estimate ,CDC20 ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Cellular localization ,Aged ,Proportional Hazards Models ,business.industry ,Cancer ,General Medicine ,Middle Aged ,Cell cycle ,Prognosis ,medicine.disease ,Immunohistochemistry ,Securin ,030104 developmental biology ,Tissue Array Analysis ,030220 oncology & carcinogenesis ,Cancer cell ,Molecular Medicine ,Female ,business - Abstract
Securin belongs to a class of cell cycle regulators that prevent metaphase-to-anaphase transition until sister chromatid separation is complete. Evidence is accumulating that securin has a prognostic impact on a variety of malignancies but, thus far, the role and regulation of securin expression and its sub-cellular localization have not been systematically addressed in breast cancer. In total 470 breast cancer specimens with follow-up data for up to 22 years were included. Immunohistochemical staining and immunofluorescence double-staining were performed for securin and its regulating proteins PTTG1IP, CDC20 and BUBR1. Prognostic associations were evaluated between the expression patterns of these proteins and established prognosticators of invasive breast cancer and patient survival. We found that a high fraction of securin expressing cancer cells predicted an unfavorable clinical outcome of the breast cancer patients (p
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- 2016
44. Inhibiting Notch Activity in Breast Cancer Stem Cells by Glucose Functionalized Nanoparticles Carrying γ-secretase Inhibitors
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Sebastian K.-J. Landor, Jessica M. Rosenholm, Veronika Mamaeva, Diti Desai, Pauliina Kronqvist, Mika Lindén, Ina Katrine Nitschke Pettersen, Michaela Beck, Ezgi Özliseli, Cecilia Sahlgren, Emmet McCormack, Tove J. Grönroos, Rasmus Niemi, Soft Tissue Biomech. & Tissue Eng., and Institute for Complex Molecular Systems
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0301 basic medicine ,Population ,Notch signaling pathway ,Antineoplastic Agents ,Breast Neoplasms ,SDG 3 – Goede gezondheid en welzijn ,ta3111 ,03 medical and health sciences ,Breast cancer ,SDG 3 - Good Health and Well-being ,Cancer stem cell ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Genetics ,medicine ,Humans ,ta318 ,Enzyme Inhibitors ,education ,Molecular Biology ,Pharmacology ,education.field_of_study ,Receptors, Notch ,Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,030104 developmental biology ,Glucose ,Biochemistry ,Cell culture ,Cancer cell ,Cancer research ,MCF-7 Cells ,Neoplastic Stem Cells ,Molecular Medicine ,Nanoparticles ,Original Article ,Female ,Stem cell ,Amyloid Precursor Protein Secretases ,Signal Transduction - Abstract
Cancer stem cells (CSCs) are a challenge in cancer treatment due to their therapy resistance. We demonstrated that enhanced Notch signaling in breast cancer promotes self-renewal of CSCs that display high glycolytic activity and aggressive hormone-independent tumor growth in vivo. We took advantage of the glycolytic phenotype and the dependence on Notch activity of the CSCs and designed nanoparticles to target the CSCs. Mesoporous silica nanoparticles were functionalized with glucose moieties and loaded with a γ-secretase inhibitor, a potent interceptor of Notch signaling. Cancer cells and CSCs in vitro and in vivo efficiently internalized these particles, and particle uptake correlated with the glycolytic profile of the cells. Nanoparticle treatment of breast cancer transplants on chick embryo chorioallantoic membranes efficiently reduced the cancer stem cell population of the tumor. Our data reveal that specific CSC characteristics can be utilized in nanoparticle design to improve CSC-targeted drug delivery and therapy. publishedVersion
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- 2016
45. Proteomic maps of breast cancer subtypes
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Matthias Mann, Stefka Tyanova, Reidar Albrechtsen, Pauliina Kronqvist, Tamar Geiger, and Juergen Cox
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0301 basic medicine ,Proteomics ,Microarray ,Science ,Quantitative proteomics ,General Physics and Astronomy ,Breast Neoplasms ,Computational biology ,Biology ,Bioinformatics ,ta3111 ,Article ,General Biochemistry, Genetics and Molecular Biology ,Transcriptome ,03 medical and health sciences ,Breast cancer ,medicine ,Humans ,Copy-number variation ,skin and connective tissue diseases ,Gene ,Multidisciplinary ,Microarray analysis techniques ,General Chemistry ,ta3121 ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Female - Abstract
Systems-wide profiling of breast cancer has almost always entailed RNA and DNA analysis by microarray and sequencing techniques. Marked developments in proteomic technologies now enable very deep profiling of clinical samples, with high identification and quantification accuracy. We analysed 40 oestrogen receptor positive (luminal), Her2 positive and triple negative breast tumours and reached a quantitative depth of >10,000 proteins. These proteomic profiles identified functional differences between breast cancer subtypes, related to energy metabolism, cell growth, mRNA translation and cell–cell communication. Furthermore, we derived a signature of 19 proteins, which differ between the breast cancer subtypes, through support vector machine (SVM)-based classification and feature selection. Remarkably, only three proteins of the signature were associated with gene copy number variations and eleven were also reflected on the mRNA level. These breast cancer features revealed by our work provide novel insights that may ultimately translate to development of subtype-specific therapeutics., Breast cancers have been extensively studied at the genomic and transcriptomic levels in the hope of tailoring therapeutic regimens. Here the authors generate deep coverage proteomes from several clinical breast cancer samples, and use machine learning techniques to uncover biological processes altered in specific cancer subtypes.
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- 2016
46. Publisher correction: Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity
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Dagmara Kaczynska, Przemysław Mitura, Shigeaki Kanatani, Per Uhlén, Kazuhiro Matsumoto, Peter Wiklund, Arne Östman, Ayako Miyakawa, Carlos Fernández Moro, Hanna Dahlstrand, Karl Deisseroth, Andrzej Stepulak, Sara Corvigno, Carina Strell, Cecilia Sahlgren, Pauliina Kronqvist, Raju Tomer, Lauri Louhivuori, Patrick Micke, Claes Lindh, Joseph W. Carlson, Artur Mezheyeuski, Loránd L. Kis, Nobuyuki Tanaka, Mototsugu Oya, Johan Hartman, Institute for Complex Molecular Systems, and Soft Tissue Biomech. & Tissue Eng.
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,Published Erratum ,Biomedical Engineering ,MEDLINE ,Medicine (miscellaneous) ,Cancer ,Bioengineering ,medicine.disease ,SDG 3 – Goede gezondheid en welzijn ,Computer Science Applications ,03 medical and health sciences ,030104 developmental biology ,Text mining ,SDG 3 - Good Health and Well-being ,medicine ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Radiology ,business ,Biotechnology ,Tissue biopsy - Abstract
In this Article originally published, owing to a technical error, author affiliations were incorrectly assigned in the HTML version; the PDF was correct. These errors have now been corrected.
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- 2018
47. Proliferation-associated miRNAs-494, -205, -21 and -126 detected by in situ hybridization: expression and prognostic potential in breast carcinoma patients
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Natalia Gurvits, Marjukka Nykänen, Kati Talvinen, Teijo Kuopio, Heli Repo, Pauliina Kronqvist, and Tuomo-Artturi Autere
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0301 basic medicine ,Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Breast Neoplasms ,In situ hybridization ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,microRNA ,Medicine ,Humans ,In Situ Hybridization ,Aged ,Cell Proliferation ,Aged, 80 and over ,Breast tissue ,Hematology ,business.industry ,General Medicine ,Cell cycle ,Middle Aged ,medicine.disease ,Prognosis ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,business ,Breast carcinoma - Abstract
To visualize by in situ hybridization (ISH) the levels of a set of proliferation-associated miRNAs and to evaluate their impact and clinical applicability in prognostication of invasive breast carcinoma. Tissue specimen from breast carcinoma patients were investigated for miRNAs-494, -205, -21 and -126. Prognostic associations for levels of miRNAs were analyzed based on complete clinical data and up to 22.5-year follow-up of the patient material (n = 285). For detection of the miRNAs, an automated sensitive protocol applying in situ hybridization was developed. MiRNA-494 indicated prognostic value for patients with invasive breast carcinoma. Among node-negative disease reduced level of miRNA-494 predicted 8.5-fold risk of breast cancer death (p = 0.04). Altered levels and expression patterns of the studied miRNAs were observed in breast carcinomas as compared to benign breast tissue. The present paper reports for the first time on the prognostic value of miRNA-494 in invasive breast cancer. Particularly, detection of miRNA-494 could benefit patients with node-negative breast cancer in identifying subgroups with aggressive disease. Based on our experience, the developed automatic ISH method to visualize altered levels of miRNAs-494, -205, -21 and -126 could be applied to routine pathology diagnostics providing that conditions of tissue treatment, especially fixation delays, are managed.
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- 2017
48. Breast cancer in neurofibromatosis type 1 : overrepresentation of unfavourable prognostic factors
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Juha Peltonen, Riikka Huovinen, Roope A. Kallionpää, Janne Pitkäniemi, Samu Kurki, Pirkko Härkönen, Minna Pöyhönen, Pauliina Kronqvist, Olli Carpén, Matti Rantanen, Elina Uusitalo, Sirkku Peltonen, Department of Public Health, University of Helsinki, Clinicum, Medicum, Department of Pathology, Precision Cancer Pathology, Department of Medical and Clinical Genetics, HUSLAB, and Minna Pöyhönen / Principal Investigator
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Colorectal cancer ,Prostate cancer ,0302 clinical medicine ,Risk Factors ,Registries ,skin and connective tissue diseases ,BENIGN-TUMORS ,Finland ,POPULATION ,Cervical cancer ,Aged, 80 and over ,RISK ,education.field_of_study ,Incidence ,WOMEN ,Middle Aged ,3142 Public health care science, environmental and occupational health ,3. Good health ,030220 oncology & carcinogenesis ,MALIGNANT NEOPLASMS ,histopathology ,Female ,Adult ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Neurofibromatosis 1 ,VONRECKLINGHAUSEN NEUROFIBROMATOSIS ,tumour suppressor ,Population ,3122 Cancers ,Breast Neoplasms ,ta3111 ,survival ,Breast Neoplasms, Male ,Cancer syndrome ,03 medical and health sciences ,Breast cancer ,breast cancer ,AGE ,Internal medicine ,medicine ,Humans ,education ,Molecular Diagnostics ,neoplasms ,cancer syndrome ,Aged ,business.industry ,MORTALITY ,hormone receptors ,medicine.disease ,ta3122 ,eye diseases ,Cancer registry ,nervous system diseases ,030104 developmental biology ,RASopathy ,NF1 ,Case-Control Studies ,prognosis ,Skin cancer ,business - Abstract
Background: An increased breast cancer incidence and poor survival have been reported for women with neurofibromatosis 1 (NF1). To explain the poor survival, we aimed to link the histopathology and clinical characteristics of NF1-associated breast cancers. Methods: The Finnish Cancer Registry and the Finnish NF Registry were cross-referenced to identify the NF1 patients with breast cancer. Archival NF1 breast cancer specimens were retrieved for histopathological typing and compared with matched controls. Results: A total of 32 breast cancers were diagnosed in 1404 NF1 patients during the follow-up. Women with NF1 had an estimated lifetime risk of 18.0% for breast cancer, and this is nearly two-fold compared with that of the general Finnish female population (9.74%). The 26 successfully retrieved archival NF1 breast tumours were more often associated with unfavourable prognostic factors, such as oestrogen and progesterone receptor negativity and HER2 amplification. However, survival was worse in the NF1 group (P = 0.053) even when compared with the control group matched for age, diagnosis year, gender and oestrogen receptor status. Scrutiny of The Cancer Genome Atlas data set showed that NF1 mutations and deletions were associated with similar characteristics in the breast cancers of the general population. Conclusions: These results emphasise the role of the NF1 gene in the pathogenesis of breast cancer and a need for active follow-up for breast cancer in women with NF1.
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- 2017
49. Cdc20 and securin overexpression predict short-term breast cancer survival
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Reino Pitkänen, Minnamaija Lintunen, Eliisa Löyttyniemi, Pauliina Kronqvist, I Ahonen, Teijo Kuopio, H Karra, Mirva Söderström, and Heli Repo
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Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Cdc20 Proteins ,Triple Negative Breast Neoplasms ,Disease ,CDC20 ,Biology ,breast cancer ,Breast cancer ,Internal medicine ,medicine ,Humans ,Cdc20 ,Molecular Diagnostics ,Aged ,Anaphase ,Aged, 80 and over ,Tissue microarray ,securin ,DNA ,Middle Aged ,ta3122 ,medicine.disease ,Neoplasm Proteins ,Spindle checkpoint ,Treatment Outcome ,Securin ,Immunology ,Female ,prognosis - Abstract
Background: Cdc20 is an essential component of cell division and responsible for anaphase initiation regulated by securin degradation. Cdc20 function is strongly regulated by the spindle assembly checkpoint to ensure the timely separation of sister chromatids and integrity of the genome. We present the first results on Cdc20 in a large clinical breast cancer material. Methods: The study was based on 445 breast cancer patients with up to 20 years of follow-up (mean 10.0 years). DNA content was determined by image cytometry on cell imprints, and Cdc20 and securin immunohistochemistry on tissue microarrays of breast cancer tissue. Results: In our results, high Cdc20 and securin expression was associated with aneuploid DNA content. In prognostic analyses, high Cdc20 immunoexpression alone and in combination with high securin immunoexpression indicated aggressive course of disease and up to 6.8-fold (P
- Published
- 2014
50. ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins
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Marie Kveiborg, Julie B. Noer, Jens Berthelsen, Pauliina Kronqvist, Marie Christine Klitgaard, Reidar Albrechtsen, Alexander Kotzsch, Carl P. Blobel, Ulla M. Wewer, Camilla Fröhlich, and Camilla Nehammer
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ADAM12 Protein ,Breast Neoplasms ,Biology ,ta3111 ,Biochemistry ,Mice ,Cell Line, Tumor ,Human Umbilical Vein Endothelial Cells ,Disintegrin ,Animals ,Humans ,Molecular Biology ,Cell Line, Transformed ,Mice, Knockout ,Neovascularization, Pathologic ,Cell adhesion molecule ,HEK 293 cells ,Membrane Proteins ,Cell Biology ,ADAM Proteins ,Gene Expression Regulation, Neoplastic ,Endothelial stem cell ,Vascular endothelial growth factor B ,HEK293 Cells ,Ectodomain ,Membrane protein ,Cancer research ,biology.protein ,Female - Abstract
ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened several membrane-anchored proteins to further dissect the substrate profile of ADAM12-mediated ectodomain shedding, and found shedding of five previously unreported substrates [Kitl1, VE-cadherin (vascular endothelial cadherin), Flk-1 (fetal liver kinase 1), Tie-2, and VCAM-1 (vascular cell adhesion molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation. In parallel, the shed form of VE-cadherin was elevated in such cytokine-stimulated endothelial cells, and ADAM12 siRNA (small interfering RNA) knockdown reduced cytokine-induced shedding of VE-cadherin. In conclusion, the results of the present study demonstrate a role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins. We speculate that this process may have importance in tumour neovascularization or/and tumour cell extravasation.
- Published
- 2013
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