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  • 1.
    Ahmadian, Afshin
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Ren, Z P
    Williams, Cecilia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Pontén, F
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Pontén, J
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Genetic instability in the 9q22.3 region is a late event in the development of squamous cell carcinoma.1998In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 17, no 14Article in journal (Refereed)
    Abstract [en]

    Squamous cell carcinoma (SCC) of the skin represents a group of neoplasms which is associated with exposure to UV light. Recently, we obtained data suggesting that invasive skin cancer and its precursors derive from one original neoplastic clone. Here, the analysis were extended by loss of heterozygosity (LOH) analysis in the chromosome 9q22.3 region. A total of 85 samples, taken from twenty-two sections of sun-exposed sites, corresponding to normal epidermis, morphological normal cells with positive immuno-staining for the p53 protein (p53 patches), dysplasias, cancer in situ (CIS) and squamous cell carcinomas (SCC) of the skin were analysed. Overall, about 70% of p53 patches had mutations in the p53 gene but not LOH in the p53 gene or 9q22.3 region. Approximately 70% of the dysplasias showed p53 mutations of which about 40% had LOH in the p53 region but not in the 9q22.3 region. In contrast, about 65% of SCC and CIS displayed LOH in the 9q22.3 region, as well as frequent (80%) mutations and/or LOH in the p53 gene. These findings strongly suggest that alterations in the p53 gene is an early event in the progression towards SCC, whereas malignant development involves LOH and alterations in at least one (or several) tumor suppressor genes located in chromosome 9q22.3.

  • 2. Ling, G
    et al.
    Ahmadian, A
    Persson, A
    Undén, A B
    Afink, G
    Williams, Cecilia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, M
    Toftgård, R
    Lundeberg, J
    Pontén, F
    PATCHED and p53 gene alterations in sporadic and hereditary basal cell cancer.2001In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 20, no 53Article in journal (Refereed)
    Abstract [en]

    It is widely accepted that disruption of the hedgehog-patched pathway is a key event in development of basal cell cancer. In addition to patched gene alterations, p53 gene mutations are also frequent in basal cell cancer. We determined loss of heterozygosity in the patched and p53 loci as well as sequencing the p53 gene in tumors both from sporadic and hereditary cases. A total of 70 microdissected samples from tumor and adjacent skin were subjected to PCR followed by fragment analysis and DNA sequencing. We found allelic loss in the patched locus in 6/8 sporadic basal cell cancer and 17/19 hereditary tumors. All sporadic and 7/20 hereditary tumors showed p53 gene mutations. Loss of heterozygosity in the p53 locus was rare in both groups. The p53 mutations detected in hereditary tumors included rare single nucleotide deletions and unusual double-base substitutions compared to the typical ultraviolet light induced missense mutations found in sporadic tumors. Careful microdissection of individual tumors revealed genetically linked subclones with different p53 and/or patched genotype providing an insight on time sequence of genetic events. The high frequency and co-existence of genetic alterations in the patched and p53 genes suggest that both these genes are important in the development of basal cell cancer.

  • 3. Ling, G.
    et al.
    Ahmadian, Afshin
    KTH, Superseded Departments, Biotechnology.
    Persson, A.
    Unden, A. B.
    Afink, G.
    Williams, C.
    Uhlén, Mathias
    KTH, Superseded Departments, Biotechnology.
    Toftgard, R.
    Lundeberg, Joakim
    KTH, Superseded Departments, Biotechnology.
    Ponten, F.
    PATCHED and p53 gene alterations in sporadic and hereditary basal cell cancer2001In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 20, no 53, p. 7770-7778Article in journal (Refereed)
    Abstract [en]

    It is widely accepted that disruption of the hedgehog-patched pathway is a key event in development of basal cell cancer. In addition to patched gene alterations, p53 gene mutations are also frequent in basal cell cancer. We determined loss of heterozygosity in the patched and p53 loci as well as sequencing the p53 gene in tumors both from sporadic and hereditary cases. A total of 70 microdissected samples from tumor and adjacent skin were subjected to PCR followed by fragment analysis and DNA sequencing. We found allelic loss in the patched locus in 6/8 sporadic basal cell cancer and 17/19 hereditary tumors. All sporadic and 7/20 hereditary tumors showed p53 gene mutations. Loss of heterozygosity in the p53 locus was rare in both groups. The p53 mutations detected in hereditary tumors included rare single nucleotide deletions and unusual double-base substitutions compared to the typical ultraviolet light induced missense mutations found in sporadic tumors. Careful microdissection of individual tumors revealed genetically linked subclones with different p53 and/or patched genotype providing an insight on time sequence of genetic events. The high frequency and co-existence of genetic alterations in the patched and p53 genes suggest that both these genes are important in the development of basal cell cancer.

  • 4. Orre, L. M.
    et al.
    Panizza, E.
    Kaminskyy, V. O.
    Vernet, Erik
    KTH, School of Biotechnology (BIO), Protein Technology.
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Protein Technology.
    Zhivotovsky, B.
    Lehtiö, J.
    S100A4 interacts with p53 in the nucleus and promotes p53 degradation2013In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 49, p. 5531-5540Article in journal (Refereed)
    Abstract [en]

    S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.

  • 5. Pontén, F
    et al.
    Berg, Cecilia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Ahmadian, A
    Ren, Z P
    Nistér, M
    Lundeberg, J
    Uhlén, M
    Pontén, J
    Molecular pathology in basal cell cancer with p53 as a genetic marker.1997In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 15, no 9Article in journal (Refereed)
    Abstract [en]

    Human basal cell cancer (BCC) has unique growth characteristics with virtual inability to metastasize. We investigated clonality and genetic progression using p53 mutations as marker. Sampling was done through microdissection of frozen immunohistochemically stained 16 microm slices of tumors. From 11 BCC tumors 78 samples were analysed. Direct DNA sequencing of exons 5-8 was performed, haplotypes were determined after cloning of p53 exons and loss of heterozygosity (LOH) ascertained by microsatellite analysis. All tumors had p53 mutations and in a majority both p53 alleles were affected, commonly through missense mutations. Microdissection of small parts (50-100 cells) of individual tumors showed BCC to be composed of a dominant cell clone and prone to genetic progression with appearance of subclones with a second and even third p53 mutation. Samples from normal immunohistochemically negative epidermis always showed wild type sequence, except for a case of previously unknown germline p53 mutation. Our analysis also included p53 immunoreactive patches i.e. morphologically normal epidermis with a compact pattern of p53 immunoreactivity. Mutations within those were never the same as in the adjacent BCC. This detailed study of only one gene thus uncovered a remarkable heterogeneity within a tumor category famous for its benign clinical behavior.

  • 6.
    Williams, Cecilia
    et al.
    Karolinska Institutet.
    Edvardsson, K
    Lewandowski, S A
    Ström, A
    Gustafsson, J-A
    A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells.2008In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, no 7, p. 1019-1032Article in journal (Refereed)
    Abstract [en]

    Transcriptional effects of estrogen result from its activation of two estrogen receptor (ER) isoforms; ERalpha that drives proliferation and ERbeta that is antiproliferative. Expression of ERbeta in xenograft tumors from the T47D breast cancer cell line reduces tumor growth and angiogenesis. If ERbeta can halt tumor growth, its introduction into cancers may be a novel therapeutic approach to the treatment of estrogen-responsive cancers. To assess the complete impact of ERbeta on transcription, we have made a full transcriptome analysis of ERalpha- and ERbeta-mediated gene regulation in T47D cell line with Tet-Off regulated ERbeta expression. Of the 35 000 genes and transcripts analysed, 4.1% (1434) were altered by ERalpha activation. Tet withdrawal and subsequent ERbeta expression inhibited the ERalpha regulation of 998 genes and, in addition, altered expression of 152 non-ERalpha-regulated genes. ERalpha-induced and ERbeta-repressed genes were involved in proliferation, steroid/xenobiotic metabolism and ion transport. The ERbeta repressive effect was further confirmed by proliferation assays, where ERbeta was shown to completely oppose the ERalpha-E2 induced proliferation. Additional analysis of ERbeta with a mutated DNA-binding domain revealed that this mutant, at least for a quantity of genes, antagonizes ERalpha even more strongly than ERbeta wt. From an examination of the genes regulated by ERalpha and ERbeta, we suggest that introduction of ERbeta may be an alternative therapeutic approach to the treatment of certain cancers.

  • 7. Zhu, J
    et al.
    Zhao, C
    Kharman-Biz, A
    Zhuang, T
    Jonsson, P
    Liang, N
    Williams, Cecilia
    University of Houston, United States .
    Lin, C-Y
    Qiao, Y
    Zendehdel, K
    Strömblad, S
    Treuter, E
    Dahlman-Wright, K
    The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation.2014In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 33, no 34, p. 4340-4351Article in journal (Refereed)
    Abstract [en]

    Estrogen receptor α (ERα) is initially expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression by regulating the transcription of genes linked to cell proliferation. ERα status is of clinical importance, as ERα-positive breast cancers can be successfully treated by adjuvant therapy with antiestrogens or aromatase inhibitors. Complications arise from the frequent development of drug resistance that might be caused by multiple alterations, including components of ERα signaling, during tumor progression and metastasis. Therefore, insights into the molecular mechanisms that control ERα expression and stability are of utmost importance to improve breast cancer diagnostics and therapeutics. Here we report that the atypical E3 ubiquitin ligase RNF31 stabilizes ERα and facilitates ERα-stimulated proliferation in breast cancer cell lines. We show that depletion of RNF31 decreases the number of cells in the S phase and reduces the levels of ERα and its downstream target genes, including cyclin D1 and c-myc. Analysis of data from clinical samples confirms correlation between RNF31 expression and the expression of ERα target genes. Immunoprecipitation indicates that RNF31 associates with ERα and increases its stability and mono-ubiquitination, dependent on the ubiquitin ligase activity of RNF31. Our data suggest that association of RNF31 and ERα occurs mainly in the cytosol, consistent with the lack of RNF31 recruitment to ERα-occupied promoters. In conclusion, our study establishes a non-genomic mechanism by which RNF31 via stabilizing ERα levels controls the transcription of estrogen-dependent genes linked to breast cancer cell proliferation.

  • 8. Zhu, J.
    et al.
    Zhao, C.
    Zhuang, T.
    Jonsson, P.
    Sinha, I.
    Williams, Cecilia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Strömblad, S.
    Dahlman-Wright, K.
    RING finger protein 31 promotes p53 degradation in breast cancer cells2016In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 15, p. 1955-1964Article in journal (Refereed)
    Abstract [en]

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

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