Jorma Isola

University of Tampere, Tammerfors, Pirkanmaa, Finland

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Publications (205)1101.03 Total impact

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    ABSTRACT: Individually submitted prostatic needle biopsies are recommended by most guidelines because of their potential advantage in terms of core quality. However, unspecified bilateral biopsies are commonly submitted in many centers. The length of the core is the key quality indicator of prostate biopsies. Because there are few recent publications comparing the quality of 12 site-designated biopsies versus pooled biopsies, we compared the lengths of the biopsies obtained by both methods. The material was obtained from 471 consecutive subjects who underwent prostatic needle biopsy in the Tampere University Hospital district between January and June 2013. Biopsies from 344 subjects fulfilled the inclusion criteria. The total number of cores obtained was 4047. The core lengths were measured on microscope slides. Extraprostatic tissue was subtracted from the core length. The aggregate lengths observed were 129.5 ± 21.8 mm (mean ± SD) for site-designated cores and 136.9 ± 26.4 mm for pooled cores (p = 0.09). The length of the core was 10.8 ± 1.8 mm for site-designated cores and 11.4 ± 2.2 mm for pooled cores (p = 0.87). The median length for pooled cores was 11 mm (range 5 mm - 18 mm). For individual site-designated cores, the median length was 11 mm (range 7 mm -15 mm). The core length was not correlated with the number of cores embedded into one paraffin block (r = 0.015). There was no significant difference in cancer detection rate (p = 0.62). Our results suggest that unspecified bilateral biopsies do not automatically lead to reduced core length. We conclude that carefully embedded multiple (three to nine) cores per block may yield cores of equal quality in a more cost-efficient way and that current guidelines favoring individually submitted cores may be too strict.
    BMC Clinical Pathology 12/2015; 15(1):4. DOI:10.1186/s12907-015-0001-9
  • Cancer Research 05/2015; 75(9 Supplement):P5-02-01-P5-02-01. DOI:10.1158/1538-7445.SABCS14-P5-02-01 · 9.28 Impact Factor
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    ABSTRACT: Mutations in the BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Ovarian cancer risk can be decreased by risk-reducing salpingo-oophorectomy (RRSO). Studies on RRSO material have altered the paradigm of serous ovarian cancer pathogenesis. The purpose of this study was to identify candidate genes possibly involved in the pathogenesis of serous ovarian cancer by carrying out a microarray analysis of differentially expressed genes in BRCA1/2- mutation positive ovarian and fallopian tube epithelium derived from RRSO surgery. Freshly frozen ovarian and fallopian tube samples from nine BRCA1/2 mutation carriers scheduled for RRSO were prospectively collected together with five mutation-negative control patients undergoing salpingo-oophorectomy for benign indications. Microarray analysis of genome-wide gene expression was performed on ovarian and fallopian tube samples from the BRCA1/2 and control patients. The validation of microarray data was performed by quantitative real-time polymerase chain reaction (qRT-PCR) in selected cases of RRSO samples and also in high grade serous carcinoma samples collected from patients with a BRCA phenotype. From 22,733 genes, 454 transcripts were identified that were differentially expressed in BRCA1/2 mutation carriers when compared with controls, pooling all ovarian and fallopian tube samples together. Of these, 299 genes were statistically significantly downregulated and 155 genes upregulated. Differentially expressed genes in BRCA1/2 samples reported here might be involved in serous ovarian carcinogenesis and provide interesting targets for further studies. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 02/2015; 54(5). DOI:10.1002/gcc.22241 · 3.84 Impact Factor
  • American Journal Of Pathology 02/2015; 185(4). DOI:10.1016/j.ajpath.2014.12.018 · 4.60 Impact Factor
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    ABSTRACT: In this paper, we address the epidemiology and morphology questions of breast cancer with special focus on different cell features created by lesions. In addition, we provide an insight into feature extraction and classification schemes in the image analysis pipeline. Based on our conducted research work, a novel feature extraction approach, a modification of Distance Transform on Curved Space (DTOCS), is proposed for analysis and classification of breast cancer images. The first experimental results suggest that the Step-DTOCS-based MLP-network is capable of discriminating different cell structures in a respectable way. The obtained results are presented and analyzed, and further research ideas are discussed.
    14th International Conference on Hybrid Intelligent Systems (HIS), Kuwait; 12/2014
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    ABSTRACT: Mutations in BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Increased lifetime ovarian cancer risk among BRCA1/BRCA2 mutation carriers can be substantially decreased by risk-reducing salpingo-oophorectomy (RRSO), which also provides material for molecular research on early pathogenesis of serous ovarian cancer. RRSO studies have suggested fallopian tube as a primary site of serous high-grade ovarian cancer. In this study, the nuclear expression levels of γ-H2AX and p53 using immunohistochemical (IHC) study was quantitatively assessed in ovarian and fallopian tube epithelium derived from RRSOs in 29 BRCA1 and BRCA2 mutation carriers and in 1 patient with a strong family history of breast and ovarian cancer but showing an unknown BRCA status. Both p53 and γ-H2AX nuclear staining levels were significantly higher in BRCA1/2 mutation-positive fallopian tube epithelium compared with the control fallopian tube epithelium (P<0.006 and P=0.011, respectively). Nuclear expression levels of p53 and γ-H2AX were similar between the BRCA1/2 mutation-positive ovarian epithelium and controls. Both γ-H2AX and p53 showed significantly higher nuclear expression levels in BRCA1/2 mutation-positive fallopian tube epithelium compared with BRCA1/2 mutation-positive ovarian epithelium (P<0.0001 and P<0.0001, respectively). BRCA1/2 mutation-positive fallopian tube epithelium showed a positive correlation between the γ-H2AX and p53 nuclear expression levels (Pearson r=0.508, P=0.003). Our results of quantitative nuclear p53 and γ-H2AX expression levels in ovarian and fallopian tube epithelium derived from RRSO in high-risk patients support the previously suggested role of fallopian tube epithelium serving as a possible site of initial serous ovarian carcinogenesis.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 03/2014; 33(3). DOI:10.1097/PGP.0b013e31829c673b · 1.63 Impact Factor
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    Mark Barok, Heikki Joensuu, Jorma Isola
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    ABSTRACT: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced breast cancer. T-DM1 is currently being evaluated as adjuvant treatment for early breast cancer. It has several mechanisms of action consisting of the anti-tumor effects of trastuzumab and those of DM1, a cytotoxic anti-microtubule agent released within the target cells upon degradation of the human epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. The cytotoxic effect of T-DM1 likely varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to T-DM1. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance. The mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of trastuzumab to cancer cells may be involved. The cytotoxic effect of T-DM1 may be impaired by inefficient internalization or enhanced recycling of the HER2-T-DM1 complex in cancer cells, or impaired lysosomal degradation of trastuzumab or intracellular trafficking of HER2. The effect of T-DM1 may also be compromised by multidrug resistance proteins that pump DM1 out of cancer cells. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations of T-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1.
    Breast cancer research: BCR 03/2014; 16(2):R22. DOI:10.1186/bcr3621 · 5.88 Impact Factor
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    ABSTRACT: Preoperative evaluation of the risk for metastases in endometrial carcinoma is challenging. The growth of new vessels, angiogenesis, is important for tumor growth and purported to be involved in the metastatic process. The aim of this study was to evaluate the significance of preoperative serum levels and immunohistochemical expression of angiogenic markers in predicting a metastasized disease. Preoperative sera from 98 consecutive women presenting with endometrial carcinoma were collected. Serum concentrations of VEGF, sFLT1, and CD105 were assessed by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to assess the expression of CD105, VEGF, FLT1, and KDR. The results were correlated to the presence of metastases, presence of deep (≥50 %) myometrial invasion, and the histological grade of the tumor. Tumors with other than endometrioid histology were excluded. Of the 80 evaluable patients, 11 had a metastasized disease. The serum concentration of VEGF was higher in the group with metastases than in the group without metastases (median [range], 743 pg/mL [546-1,183 pg/mL] vs. 383 pg/mL [31-1,524 pg/mL], p < 0.001, respectively). In the multivariable analysis, the concentration of VEGF was the sole independent, albeit weak predictive factor for the presence of metastases (odds ratio, 1.004, 95 % confidence interval, 1.002-1.007; p = 0.001). The immunohistochemical expression of the markers was not associated with any of the clinicopathological features of the tumors. The results of the present study suggest that preoperative serum VEGF concentration correlates with the presence of metastases in endometrioid endometrial carcinoma.
    Tumor Biology 01/2014; 35(5). DOI:10.1007/s13277-014-1609-6 · 2.84 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):869-869. DOI:10.1158/1538-7445.AM2013-869 · 9.28 Impact Factor
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    ABSTRACT: Formalin fixation preserves tissue morphology at the expense of macromolecule integrity. Freshly frozen samples are the golden standard for DNA and RNA analyses but require laborious deep-freezing and frozen sectioning for morphological studies. Alternative tissue stabilisation methods are therefore needed. We analysed the preservation of nucleic acids, immunohistochemical staining properties and tissue morphology in paraffin-embedded clinical tissue samples fixed with Z7, RCL2, PAXgene, Allprotect and RNAlater. Formalin-fixed and deep-frozen samples were used as controls. Immunohistochemical analyses showed good preservation of antigenicity in all except Allprotect and RNAlater-fixed samples. RNA quality, based on RNA integrity number value by Bioanalyzer, was comparable with freshly frozen samples only in PAXgene-fixed samples. According to quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses, RNA from PAXgene samples yielded results similar to freshly frozen samples. No difference between fixatives was seen in DNA analyses (PCR and real-time PCR). In conclusion, PAXgene seems to be superior to other molecular fixatives and formaldehyde.
    Journal of clinical pathology 06/2013; 66(9). DOI:10.1136/jclinpath-2012-201283 · 2.55 Impact Factor
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    ABSTRACT: Gremlin 1 and noggin are inhibitors of bone morphogenetic protein (BMP) signaling. They are vital during early development but their role in adult tissues has remained largely unresolved. The BMP signaling pathway has also been implicated in tumorigenesis, however with emphasis on the role of the ligands and receptors. We performed a concurrent survey of gremlin 1 and noggin protein expression in multiple normal and cancer samples, using immunohistochemistry on tissue microarrays containing 96 samples from 34 different normal organs/tissue sites and 208 samples of 34 different tumor types. In majority of both normal and tumor samples, gremlin 1 and noggin expression was negative or weak. However, normal stomach and skin demonstrated distinct gremlin 1 and noggin expression indicating a role in adult tissues. Likewise, strong expression of both antagonists was detected in Leydig cells of testis. In the tumor panel, the expression patterns were more variable but elevated BMP antagonist expression was detected for the first time in few cases, such as glioblastoma, hepatocellular carcinoma and diffuse B-cell lymphoma for gremlin 1 and renal granular cell tumor and thyroid papillary carcinoma for noggin. Even though gremlin 1 and noggin were not widely expressed in adult tissues, in a subset of organs their expression pattern indicated a potential role in normal tissue homeostasis as well as in malignancies.
    International journal of clinical and experimental pathology 01/2013; 6(7):1400-8. · 1.78 Impact Factor
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    ABSTRACT: Background Disseminated tumour cells (DTCs) in the bone marrow of patients with breast cancer have been identified as an independent predictor of poor prognosis in patients with non-metastatic disease. This prospective study aimed to evaluate the presence and prognostic value of DTCs in the bone marrow of female patients with primary breast cancer. Methods Between 1999 and 2003, bone marrow aspirates were obtained from patients at the time of surgery for primary invasive breast cancer. DTCs in bone marrow were identified using monoclonal antibodies against cytokeratins for detection of epithelial cells. The detection of DTCs was related to clinical follow-up with distant disease-free survival (DDFS) and breast cancer-specific survival as endpoints. Bone marrow aspirates from adult healthy bone marrow donors were analysed separately. Results DTCs were analysed in 401 patients, and cytokeratin-positive cells were found in 152 of these (38%). An immunofluorescence (IF) staining procedure was used in 327 patients, and immunocytochemistry (IC) was performed in 74 patients. The IF-based method resulted in 40% DTC-positive cases, whereas 30% were positive using IC (p = 0.11). The presence of DTCs in bone marrow was not significantly related to patient or tumour characteristics. The presence of DTCs was not a prognostic factor for DDFS (IF: hazards ratio [HR], 2.2; 95% confidence interval [CI], 0.63–2.2; p = 0.60; IC: HR, 0.84; 95% CI, 0.09–8.1; p = 0.88). Significant prognostic factors were lymph node metastases, oestrogen receptor positivity, Nottingham histological grade, and tumour size using Cox univariate analysis. The analyses were positive for epithelial cells in bone marrow from adult healthy donors in 19 (25%) samples. Conclusions The detection of DTCs in bone marrow in primary breast cancer was previously shown to be a predictor of poor prognosis. We were not able to confirm these results in a prospective cohort including unselected patients before the standard procedure was established. Future studies with a standardised patient protocol and improved technique for isolating and detecting DTCs may reveal the clinical applications of DTC detection in patients with micrometastases in the bone marrow.
    BMC Cancer 09/2012; 12(1):403. DOI:10.1186/1471-2407-12-403 · 3.32 Impact Factor
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    ABSTRACT: The ATP-binding cassette (ABC) of active transporters comprises a group of proteins that which facilitate efflux of anticancer drugs from cancer cells. We focused on the gene amplification and protein expression of ABCC3 (also known as MRP3) in breast cancer cell lines and clinical tumor samples. Fluorescence and chromogenic in situ hybridization, using an ABCC3-specific probe, was used to analyze 11 breast cancer cell lines and 112 clinical tumor samples. The results of ABCC3 were correlated with the amplification status of HER2 and topoisomerase II alpha (TOP2A), which are located close to ABCC3 at 17q12-q21. Immunohistochemistry was used to assess ABCC3 protein overexpression. Of the cell lines studied 6 HER2-positive lines and 1 HER2-negative line exhibited amplification of ABCC3. In the HER-2-negative clinical tumor samples, only 4/55 (7.3%) exhibited ABCC3 amplification. In the HER2-positive tumors, ABCC3 was amplified in 16/57 tumors (28.1%, P=0.0059). TOP2A did not exhibit any consistent coamplification pattern. ABCC3 (MRP3) protein overexpression was more common in tumors with gene amplification (P=0.069). In silico analysis of 804 breast cancers with matched gene expression and copy number microarray data revealed significant differences ABCC3 across the molecular subtypes. Specifically, increased ABCC3 mRNA and gene copy numbers were most prominent in HER2 amplified and/or HER2-enriched classified tumors. Moreover, differential ABCC3 mRNA levels were found within the HER-2 amplified subset when stratified by the estrogen receptor status. We conclude that ABCC3 is frequently amplified and overexpressed in HER2-positive breast cancer, and something that warrants further studies correlating the results with therapeutic outcome.
    Genes Chromosomes and Cancer 09/2012; 51(9):832-40. DOI:10.1002/gcc.21967 · 3.84 Impact Factor
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    ABSTRACT: Gastrointestinal and pancreatic neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells, expressing general and specific neuroendocrine markers. The World Health Organization 2010 classification of NETs is based on grading them according to the proliferation index (PI), which is determined by immunohistochemical staining of the nuclear antigen Ki-67. The classification introduces Ki-67 as the most important criterion for tumor grading, influencing patients' prognoses and the choice of treatment. The aim of this study was to evaluate the assessment of PI value in NETs and its influence on tumor grading. The tumor material consisted of 51 NETs from the pancreas (n=31) and ileum (n=20). The slides were stained with the Ki-67 antibody and visualized using a polymer kit. PI was assessed visually by microscope oculars and using a public domain image analysis software, ImmunoRatio. The PI was measured from the most proliferative areas of the tumor. The PI values and tumor grade by ImmunoRatio were highly reproducible as compared with conventional assessment, which suffered from variation especially if ascertained by different observers. Computer-aided assessments had almost perfect correlation (r=0.985, r=0.987, and r=0.995) (P=0.000) and reproducibility (κ=0.886, κ=0.886, and κ=1.000) (P=0.000) in PI values and tumor grades, respectively. The PI values and tumor grade between conventional and ImmunoRatio assessments by a qualified observer were in good agreement. ImmunoRatio is a qualified diagnostic aid to more objectively analyze Ki-67 PI-based tumor grade in NETs.
    The American journal of surgical pathology 09/2012; 36(9):1359-63. DOI:10.1097/PAS.0b013e3182632038 · 4.59 Impact Factor
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    ABSTRACT: Endocrine therapy by castration or anti-androgens is the gold standard treatment for advanced prostate cancer. Although it has been used for decades, the molecular consequences of androgen deprivation are incompletely known and biomarkers of its resistance are lacking. In this study, we studied the molecular mechanisms of hormonal therapy by comparing the effect of bicalutamide (anti-androgen), goserelin (GnRH agonist) and no therapy, followed by radical prostatectomy. For this purpose, 28 men were randomly assigned to treatment groups. Freshly frozen specimens were used for gene expression profiling for all known protein-coding genes. An in silico Bayesian modelling tool was used to assess cancer-specific gene expression from heterogeneous tissue specimens. The expression of 128 genes was > two-fold reduced by the treatments. Only 16% of the altered genes were common in both treatment groups. Of the 128 genes, only 24 were directly androgen-regulated genes, according to re-analysis of previous data on gene expression, androgen receptor-binding sites and histone modifications in prostate cancer cell line models. The tumours containing TMPRSS2-ERG fusion showed higher gene expression of genes related to proliferation compared to the fusion-negative tumours in untreated cases. Interestingly, endocrine therapy reduced the expression of one-half of these genes and thus diminished the differences between the fusion-positive and -negative samples. This study reports the significantly different effects of an anti-androgen and a GnRH agonist on gene expression in prostate cancer cells. TMPRSS2-ERG fusion seems to bring many proliferation-related genes under androgen regulation.
    The Journal of Pathology 07/2012; 227(3):336-45. DOI:10.1002/path.4027 · 7.33 Impact Factor
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    Gynecologic Oncology 04/2012; 125(1):282–283. DOI:10.1016/j.ygyno.2011.12.437 · 3.69 Impact Factor
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    ABSTRACT: Assessment of the human epidermal growth factor receptor 2 (HER2) with immunohistochemistry (IHC) is routine practice in clinical pathology laboratories. Visual classification of the staining reaction (usually into 0/1+, 2+ or 3+) is subjective and prone to significant inter- and intra-observer variation. In this study, we describe ImmunoMembrane, an easy-to-use HER2 IHC analysis software, which is freely available as a web application, requiring no download or installation. ImmunoMembrane uses colour deconvolution for stain separation and a customized algorithm for cell membrane segmentation. A quantitative score (IM-score, 0-20 points) is generated according to the membrane staining intensity and completeness. Specimens are classified into 0/1+, 2+ or 3+ based on IM-score cut-offs defined using a training set. The classification and membrane segmentation are presented as a pseudo-coloured overlay image. With a validation set (144 HercepTest(®) -stained whole tissue sections), ImmunoMembrane matched well with the pathologist's visual classification (weighted kappa κ(w) =0.80), as well as fluorescence in-situ hybridization (FISH) (IHC disagreement 3.5%, n=144) and chromogenic in-situ hybridization (CISH) (IHC disagreement 2.8%, n=144). We anticipate that publicly available web applications, such as ImmunoMembrane, will accelerate the adoption of automated image analysis in clinical diagnostics of HER2 IHC. ImmunoMembrane is freely accessible at:
    Histopathology 02/2012; 60(5):758-67. DOI:10.1111/j.1365-2559.2011.04142.x · 3.30 Impact Factor
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    ABSTRACT: Previous studies of breast cancer have shown that patients whose tumors are detected by mammography screening have a more favorable survival. Little is known, however, about the long-term prognostic impact of screen detection. The purpose of the current study was to compare breast cancer-specific long-term survival of patients whose tumors were detected in mammography screening compared with those whose tumors were detected by other methods. Breast cancer patients diagnosed within five specified geographical areas in Finland in 1991 and 1992 were identified (N = 2,936). Detailed clinical, treatment and outcome data, as well as tissue samples, were collected. Women with in situ carcinoma, distant metastases at the time of primary diagnosis and women who were not treated surgically were excluded. The main analyses were performed after excluding patients with other malignancy or contralateral breast cancer, followed by sensitivity analyses with different exclusion criteria. Median follow-up time was 15.4 years. Univariate and multivariate analyses of breast cancer-specific survival were performed. Of patients included in the main analyses (n = 1,884), 22% (n = 408) of cancers were screen-detected and 78% (n = 1,476) were detected by other methods. Breast cancer-specific 15-year survival was 86% for patients with screen-detected cancer and 66% for patients diagnosed using other methods (P < 0.0001, HR = 2.91). Similar differences in survival were observed in women at screening age (50 to 69 years), as well as in clinically important subgroups, such as patients with small tumors (≤ 1 cm in diameter) and without nodal involvement (N0). Women with breast cancer diagnosed on the basis of screening mammography had a more favorable prognosis than those diagnosed outside screening programs, following adjustments according to patient age, tumor size, axillary lymph node status, histological grade and hormone receptor status. Significant differences in the risk of having future contralateral breast cancer according to method of detection were not observed. Breast cancer detected by mammography screening is an independent prognostic factor in breast cancer and is associated with a more favorable survival rate as well as in long-term follow-up.
    Breast cancer research: BCR 12/2011; 13(6):R134. DOI:10.1186/bcr3080 · 5.88 Impact Factor
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    ABSTRACT: Our previous microarray study showed that the non-specific cytotoxic cell receptor protein 1 (Nccrp1) transcript is significantly upregulated in the gastric mucosa of carbonic anhydrase IX (CA IX)-deficient (Car9(-/-)) mice. In this paper, we aimed to characterize human NCCRP1 and to elucidate its relationship to CA IX. Recombinant NCCRP1 protein was expressed in Escherichia coli, and a novel polyclonal antiserum was raised against the purified full-length protein. Immunocytochemistry showed that NCCRP1 is expressed intracellularly, even though it has previously been described as a transmembrane protein. Using bioinformatic analyses, we identified orthologs of NCCRP1 in 35 vertebrate genomes, and up to five paralogs per genome. These paralogs are FBXO genes whose protein products are components of the E3 ubiquitin ligase complexes. NCCRP1 proteins have no signal peptides or transmembrane domains. NCCRP1 has mainly been studied in fish and was thought to be responsible for the cytolytic function of nonspecific cytotoxic cells (NCCs). Our analyses showed that in humans, NCCRP1 mRNA is expressed in tissues containing squamous epithelium, whereas it shows a more ubiquitous tissue expression pattern in mice. Neither human nor mouse NCCRP1 expression is specific to immune tissues. Silencing CA9 using siRNAs did not affect NCCRP1 levels, indicating that its expression is not directly regulated by CA9. Interestingly, silencing NCCRP1 caused a statistically significant decrease in the growth of HeLa cells. These studies provide ample evidence that the current name, "non-specific cytotoxic cell receptor protein 1," is not appropriate. We therefore propose that the gene name be changed to FBXO50.
    PLoS ONE 11/2011; 6(11):e27152. DOI:10.1371/journal.pone.0027152 · 3.53 Impact Factor
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    ABSTRACT: S100P is a member of the S100 family of calcium-binding proteins involved in calcium sensing and signal transduction. Its abnormal expression and biological activities are linked to tumor phenotype, namely to increased survival, proliferation, invasion and metastatic propensity of tumor cells. Association of S100P with outcome of tumor treatment and preliminary data from S100P promoter analysis prompted us to study regulation of S100P expression by glucocorticoids, which are implicated in tumor response to chemotherapy. We showed that dexamethasone (DX), a representative glucocorticoid, was capable to induce activity of S100P promoter by means of increased expression, nuclear translocation, and transactivation properties of the glucocorticoid receptor (GR). Moreover, DX treatment led to decreased phosphorylation of ERK1/2, reduced transcriptional activity of AP1, and modulated activity of some additional transcription factors. We identified a promoter region responsible for DX-mediated transactivation and proved GR binding to S100P promoter. We found that the effect of DX was enhanced by partial but not complete inhibition of the MAPK/ERK pathway, supporting an active crosstalk between GR and MAPK/ERK signal transduction in control of S100P expression. On the other hand, suppression of GR mRNA level by transient siRNA expression resulted in reduced S100P transcription. The role of GR activation in S100P regulation was supported by co-expression of GR with S100P in cells treated with DX. These data suggest that S100P is a direct transcriptional target of glucocorticoid-mediated signaling in tumor cells that is activated through the interplay of GR and MAPK pathways.
    Journal of Cellular Biochemistry 11/2011; 112(11):3373-84. DOI:10.1002/jcb.23268 · 3.37 Impact Factor

Publication Stats

12k Citations
1,101.03 Total Impact Points


  • 1987–2015
    • University of Tampere
      • • Institute of Medical Technology
      • • Institute of Biomedical Technology
      • • Laboratory of Cancer Genetics
      • • Department of Oncology
      • • Department of Biomedical Sciences
      Tammerfors, Pirkanmaa, Finland
  • 2008–2009
    • Columbia University
      • • College of Physicians and Surgeons
      • • Institute of Cancer Genetics
      New York, New York, United States
  • 2002–2009
    • Helsinki University Central Hospital
      • Department of Oncology
      Helsinki, Uusimaa, Finland
    • Helsingborgs Lasarett
      Hälsingborg, Skåne, Sweden
  • 1993–2008
    • Tampere University Hospital (TAUH)
      Tammerfors, Province of Western Finland, Finland
  • 2006
    • University of Turku
      • MediCity Research Laboratory
      Turku, Western Finland, Finland
  • 2001–2006
    • University of Helsinki
      • • Department of Oncology
      • • Department of Chemistry
      Helsinki, Uusimaa, Finland
  • 1999–2003
    • Lund University
      • Department of Oncology
      Lund, Skane, Sweden
  • 2000
    • Tampere University of Technology
      Tammerfors, Pirkanmaa, Finland
    • Karolinska University Hospital
      • Department of Surgery
      Tukholma, Stockholm, Sweden
  • 1997
    • University of California, San Francisco
      San Francisco, California, United States